Small molecule inhibitors of necroptosis

ABSTRACT

The invention features a series of heterocyclic derivatives that inhibit tumor necrosis factor alpha (TNF-α) induced necroptosis. The heterocyclic compounds of the invention are described by Formulas (I)-(VIII) and by Compounds (I)-(I), (13)-(26), (27)-(33), (48)-(57), and (58)-(70). These necrostatins are shown to inhibit TNF-α induced necroptosis in FADD-deficient variant of human Jurkat T cells. The invention further features pharmaceutical compositions featuring necrostatins. The compounds and compositions of the invention may also be used to treat disorders where necroptosis is likely to play a substantial role.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.61/140,615, filed Dec. 23, 2008, which is hereby incorporated byreference.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with government support under UO1 NS050560awarded by the National Institutes of Health. The U.S. government hascertain rights to this invention.

FIELD OF THE INVENTION

The invention relates to compounds and to cell death, in particularthrough necrosis and necroptosis, and regulation thereof by smallmolecules.

BACKGROUND OF THE INVENTION

In many diseases, cell death is mediated through apoptotic and/ornecrotic pathways. While much is known about the mechanisms of actionthat control apoptosis, control of necrosis is not as well understood.Understanding the mechanisms regulating both necrosis and apoptosis incells is essential to being able to treat conditions, such asneurodegenerative diseases, stroke, coronary heart disease, kidneydisease, and liver disease. A thorough understanding of necrotic andapoptotic cell death pathways is also crucial to treating AIDS and theconditions associated with AIDS, such as retinal necrosis.

Cell death has traditionally been categorized as either apoptotic ornecrotic based on morphological characteristics (Wyllie et al., Int.Rev. Cytol. 68: 251 (1980)). These two modes of cell death were alsoinitially thought to occur via regulated (caspase-dependent) andnon-regulated processes, respectively. More recent studies, however,demonstrate that the underlying cell death mechanisms resulting in thesetwo phenotypes are much more complicated and, under some circumstances,interrelated. Furthermore, conditions that lead to necrosis can occur byeither regulated caspase-independent or non-regulated processes.

One regulated caspase-independent cell death pathway with morphologicalfeatures resembling necrosis, called necroptosis, has recently beendescribed (Degterev et al., Nat. Chem. Biol. 1:112 (2005)). This mannerof cell death can be initiated with various stimuli (e.g., TNF-α and Fasligand) and in an array of cell types (e.g., monocytes, fibroblasts,lymphocytes, macrophages, epithelial cells and neurons). Necroptosis mayrepresent a significant contributor to and, in some cases, predominantmode of cellular demise under pathological conditions involvingexcessive cell stress, rapid energy loss, and massive oxidative speciesgeneration, where the highly energy-dependent apoptosis process is notoperative.

The identification and optimization of low molecular weight moleculescapable of inhibiting necroptosis will assist in elucidating its role indisease patho-physiology and could provide compounds (i.e.,necrostatins) for anti-necroptosis therapeutics. The discovery ofcompounds that prevent caspase-independent cell death (e.g., necrosis ornecroptosis) would also provide useful therapeutic agents for treatingor preventing conditions in which necrosis occurs. These compounds andmethods would be particularly useful for the treatment ofneurodegenerative diseases, ischemic brain and heart injuries, and headtrauma.

SUMMARY OF THE INVENTION

The invention features a series of heterocyclic derivatives that inhibittumor necrosis factor alpha (TNF-α) induced necroptosis. The inventionfurther features pharmaceutical compositions featuring necrostatins. Thecompounds and compositions of the invention may also be used to treatdisorders where necroptosis is likely to play a substantial role.

In a first aspect, the invention features a compound having a structureaccording to the following formula:

where

each R_(H1), R_(H2), R_(H3), R_(H4), R_(H5), R_(H10), R_(H17), X_(H2),Z_(H1), Z_(H2), and n is as defined for Formula (I),

X_(H2) is selected, independently, from O, S, or NR_(H9);

each R_(H1), R_(H2), R_(H3), R_(H4), and R_(H5) is selected,independently from H, halogen, cyano, nitro, azido, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl, optionallysubstituted C₂₋₆ alkynyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl,optionally substituted heteroaryl, —C(═O)R_(H12), —C(═O)OR_(H12),—C(═O)NR_(H12)R_(H13), —C(═S)R_(H12), —C(═S)NR_(H12)R_(H13),—C(═NR_(H14))R_(H12), —C(═NR_(H14))NR_(H12)R_(H13), or—[Z_(H1)—(CR_(H15)R_(H16))_(n)-{C(═X_(H2))}_(o)—Z_(H2)—R₁₇], or R_(H1)and R_(H3) combine to form a carbon-carbon double bond;

each Z_(H1) and Z_(H2) is selected, independently, from a single bond,O, S, or NR_(H11);

each R_(H9), R_(H10), R_(H11), R_(H12), R_(H13), R_(H14), R_(H15),R_(H16), and R_(H17), is selected, independently from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl;

n is an integer between 0-6; and

o is 0 or 1; and

when R_(H1) is H, R_(H2) is H or CO₂Me, R_(H3) is H, R_(H4) isunsubstituted phenyl or phenyl substituted with 1, 2, or 3 substituentsselected from methoxy, chloro, or fluoro, R_(H5) is CN, R_(H10) is H,Z_(H1) is S, n is 1, X_(H2) is O, and Z_(H2) is NH, R_(H17) is not H,methyl, methoxy, unsubstituted 2-thiazolyl, unsubstituted phenyl,4-methoxyphenyl, 4-methylphenyl, 2-ethoxyphenyl, 4-isopropylphenyl,4-fluorophenyl, or 2,4,6-trimethylphenyl, or any pharmaceuticallyacceptable salt or solvate thereof, or any stereoisomer thereof.

In some embodiments, the compound has a structure according to Formula(I-B)

where

each R_(H1) and R_(H3) is selected, independently, from H, halogen,cyano, nitro, azido, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl,—C(═O)R_(H12), —C(═O)OR_(H12), or —C(═O)NR_(H12)R_(H13), or R_(H1) andR_(H3) combine to form a carbon-carbon double bond;

each R_(H4) and R_(H17) is selected, independently, from optionallysubstituted aryl or optionally substituted heteroaryl;

R_(H5) is selected from H, CN, —C(═O)OR_(H12), or —C(═O)NR_(H12)R_(H13);

each R_(H10), R_(H11), R_(H12), and R_(H13) is selected from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl;

Z_(H1) is selected from a single bond or S;

Z_(H2) is selected from a single bond or NR_(H11); and

X_(H2) is O or S;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In other embodiments, the compound has the following structure:

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(H1) and R_(H3) are H.

In some embodiments, R_(H5) is CN.

In some embodiments, R_(H10) is H.

In some embodiments, Z_(H1) is S.

In some embodiments, Z_(H2) is NH,

In some embodiments, R_(H4) is unsubstituted phenyl or phenyl having 1,2, 3, 4, or 5 substituents. In further embodiments, the phenyl includes1, 2, or 3 substituents selected from F, Cl, or OR_(H18), where eachR_(H18) is, independently, selected from H or optionally substitutedC₁₋₆ alkyl. In certain embodiments, the phenyl is 2-fluorophenyl,2-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2-methoxyphenyl,3,4,5-trimethoxyphenyl, or 3,4-dimethoxyphenyl.

In some embodiments, R_(H17) is optionally substituted heteroaryl. Incertain embodiments, heteroaryl selected from furan, thiophene, pyrrole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,3-oxadiazole or1,2,5-oxadiazole, oxazole, benzoxazole, isoxazole, isothiazole,pyrazole, thiazole, benzthiazole, 1,2,4-triazole, 1,2,3-triazole,benzotriazole, pyridine, pyrimidine, pyrazines, quinoline, isoquinoline,purine, pyrazine, pteridine, 1,2,3-triazine, 1,2,4-triazine,1,3,5-triazine, indole, 1,2,4,5-tetrazine, benzo[b]thiophene,benzo[c]thiophene, benzofuran, isobenzofuran, and benzimidazole.

In a second aspect, the invention features a compound having a structureaccording to the following formula

where

each R_(A1), R_(A3), and R_(A4) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl, or R_(A1) and R_(A4) combineto form a carbon-carbon double bond;

G_(A2) is absent or —(CR_(A11)R_(A12))_(n)—;

X_(A3) is absent or is O, S, or NR_(A8);

each R_(A8) and R_(A13) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —COR_(A14), —CO₂R_(A14), or—CONR_(A14)R_(A15);

each R_(A9), R_(A10), R_(A11), and R_(A12) is selected, independently,from H, halogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

each R_(A7), R_(A14) and R_(A15) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl; and

each m and n is, independently, 1, 2, or 3; and

where when one of R_(A1) and R_(A4) is H and the other is selected fromH or CO₂Et, and R_(A3) is unsubstituted phenyl, G_(A2)-X_(A3)—R_(A7) isnot NHC₆H₅, NH(p-C₆H₄F), NH(p-C₆H₄OH), NH(p-C₆H₄OMe),NH(3-OH-4-Cl—C₆H₄), —CH₂(O-p-C₆H₄Me), —CH₂(4-ethylpiperazinyl),—CH₂S(2-phenyltetrazolyl), —CH₂S(4-chlorophenyl),—CH₂S(2-benzothiazolyl), —CH₂S(2-(N-methylimidazolye),—CH₂S(4,6-dimethylquinazolinyl), adamantyl, or optionally substitutedoxiranyl; and

where when R_(A1) and R_(A4) are each H and R_(A3) is 4-methoxyphenyl,G_(A2)-X_(A3)—R_(A7) is not optionally substituted oxiranyl;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(A1) and R_(A4) are H.

In some embodiments, R_(A3) is unsubstituted phenyl.

In some embodiments, R_(A3) is phenyl having 1, 2, 3, 4, or 5substituents.

In some embodiments, G_(A2) is absent.

In certain embodiments, X_(A3) is absent and R_(A7) is optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl.

In other embodiments, X_(A3) is NR_(A8) and R_(A7) is optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl.

In some embodiments, G_(A2) is CH₂.

In some embodiments, X_(A3) is S and R_(A7) is optionally substitutedC₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl.

In some embodiments, X_(A3) is absent and R_(A7) is optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl.

In a third aspect, the invention features compounds according to thefollowing formula

where

each R_(A1), R_(A2), R_(A4), and R_(A6) is selected, independently, fromH, —C(═O)—X_(A3)—R_(A7), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl, or R_(A1) and R_(A4) combine to form a carbon-carbon doublebond;

each X_(A3) is, independently, absent, —O—, or —NR_(A8)—,

each R_(A8) is selected, independently, from H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —COR_(A14), —CO₂R_(A14), or —CONR_(A14)R_(A15);

each R_(A7), R_(A14) and R_(A15) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl; and

-   -   wherein when R_(A1) and R_(A4) combine to form a carbon-carbon        double bond and R_(A2) is H, R_(A6) is not 4-chlorophenyl,        4-methoxyphenyl, or 4-(NHCO₂ ^(t)Bu)phenyl; and

where when R_(A1) is H, R_(A4) is H or CO₂Et, R_(A2) is unsubstitutedphenyl, R_(A6) is not —C(═O)-(unsubstituted phenyl) or—C(═O)-(4-methylphenyl); and

where when R_(A1) is H, R_(A4) is —C(═O)-(unsubstituted phenyl), R_(A2)is 4-chlorophenyl, R_(A6) is not CO₂Et;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(A5) is H; each R_(A1), R_(A2), R_(A4), andR_(A6) is selected, independently, from H, optionally substituted aryl,optionally substituted heteroaryl, —C(═O)—X_(A3)—R_(A7), or R_(A1) andR_(A4) combine to form a carbon-carbon double bond; each R_(A7) isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; and

each X_(A3) is, independently, absent, —O—, or —NR_(A8)—,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In certain embodiments, R_(A1) and R_(A4) combine to form acarbon-carbon double bond.

In other embodiments, R_(A6) is optionally substituted aryl oroptionally substituted heteroaryl.

In some embodiments, R_(A6) is a phenyl group having a substituent atthe 4-position.

In certain embodiments, R_(A1) and R_(A4) are each H, R_(A2) isoptionally substituted aryl or optionally substituted heteroaryl, andR_(A6) is —C(═O)—X_(A3)—R_(A7).

In other embodiments, R_(A2) is unsubstituted phenyl.

In a fourth aspect, the invention features a compound having a structureaccording to the following formula:

where

R_(B1) is selected from H, optionally substituted C₁₋₆ alkyl,—C(═O)R_(B18), —C(═O)OR_(B18), or —C(═O)NR_(B18)R_(B19);

R_(B2) is selected from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, or optionally substituted C₂₋₆ alkynyl;

each R_(B3) and R_(B4) is selected, independently from H, optionallysubstituted C₁₋₆ alkyl, or R_(B3) and R_(B4) combine to form a bridginggroup having the structure—(CH₂)_(n)—(CR_(B13)═CR_(B14))_(o)—(CH₂)_(p)—;

each n, o, and p is, independently, 0 or 1;

each R_(B5), R_(B6), R_(B7), R_(B8), R_(B9), R_(B10), R_(B11), andR_(B12) is selected, independently, from H, halogen, —CN, —NO₂, —N₃,—R_(B13), —OR_(B13), —SR_(B13), —NR_(B13)R_(B14), —C(═O)R_(B15),—C(═O)OR_(B15), —C(═O)NR_(B15)R_(B16), —OC(═O)R_(B15), —OC(═O)OR_(B15),—OC(═O)NR_(B15)R_(B16), —NR_(B15)C(═O)R_(B15), —NR_(B15)C(═O)OR_(B16),—NR_(B15)C(═O)NR_(B16)R_(B17), —C(═S)R_(B15), —C(═S)NR_(B15)R_(B16),—NR_(B15)C(═S)R_(B16), —NR_(B15)C(═S)NR_(B16)R_(B17),—C(═NR_(B13))NR_(B15)R_(B16), —NR_(B15)C(═NR_(B13))R_(B16),—NR_(B15)C(═NR_(B13))NR_(B16)R_(B17);

each R_(B13) and R_(B14) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,—C(═O)R_(B18), —C(═O)OR_(B18), or —C(═O)NR_(B18)R_(B19),

each R_(B15), R_(B16), R_(B17), R_(B18), and R_(B19) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl;

where when each n, o, and p is 0, R_(B3) and R_(B4) combine to form asingle bond, and

where R_(B1) is not H or CH₃ when R_(B5), R_(B6), R_(B7), R_(B8),R_(B9), R_(B10), R_(B11), and R_(B12) are each H, R_(B2) is ethyl,ethenyl, 2-haloethenyl, ethynyl, haloethynyl, propynyl, or—C≡C—C(OH)(CH₃)₂, and when R_(B3) and R_(B4) are each H or combine toform a bond, —CH₂CH₂— or —CH═CH—;

where R_(B1) is not H when R_(B5), R_(B6), R_(B7), R_(B8), R_(B10), andR_(B11) are each H, at least one of R_(B9) or R_(B12) is fluoro, R_(B2)is ethynyl, and when R_(B3) and R_(B4) combine to form —CH₂CH₂—;

wherein R_(B1) is not H when R_(B5), R_(B7), R_(B9), and R_(B11) are Hand one or two of R_(B6), R_(B8), R_(B10), and R_(B12) is halogen,nitro, or methyl;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(B1) is H.

In some embodiments, R_(B2) is C₁₋₃ alkyl.

In certain embodiments, R_(B2) is C₁₋₃ alkenyl.

In other embodiments, R_(B2) is ethynyl.

In some embodiments, R_(B3) and R_(B4) are each H.

In certain embodiments, the compound has the following structure

whereR_(B2) is ethyl, ethenyl, or ethynyl and each R_(B9), R_(B10), R_(B11),and R_(B12) is selected, independently, from H and halogen, or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof. In some embodiments, R_(B10) or R_(B12) is fluoro.

In some embodiments, the compound has the following structure:

where

R_(B2) is ethyl, ethenyl, or ethynyl and each R_(B9), R_(B10), R_(B11),and R_(B12) is selected, independently, from H and halogen, or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof.

In a fifth aspect, the invention features a structure according to thefollowing formula

where

each R_(C1), R_(C2), and R_(C3) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, —Y—R_(C7), or R_(C1) and R_(C2)combine to form a (═O) or a (═S) group, or R_(C1) and R_(C3) combine toform a carbon-nitrogen double bond;

R_(C4) is selected from H, halogen, —CN, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, or —C(═O)ZR_(C8),

each R_(C5) and R_(C6) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, or R_(C5) and R_(C6) combine to form anoptionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

each R_(C7), R_(C8), R_(C9), R_(C10), R_(C11), and R_(C12) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl;

X is —CR_(C11)═CR_(C12)—, O, S, or NR_(C9);

Y is, independently, a single bond, (CR_(C8)R_(C9))_(n), O, S, orNR_(C10); and

Z is a single bond, O, S, or NR_(C10);

n is an integer between 0-4; and

where when X is S, R_(C1) and R_(C2) combine to form a (═O) group,R_(C4) is H, and R_(C5) and R_(C6) combine to form unsubstitutedcyclopentyl, R_(C3) is not —CH₂—R_(C7), where R_(C7) is unsubstitutedphenyl, unsubstituted naphthyl, unsubstituted 8-quinolyl, unsubstituted2-oxoquinolyl, or phenyl having 1 or 2 substituents selected from F,OMe, Me, CN, or Cl; and

wherein when X is S, R_(C1) and R_(C2) combine to form a (═O) group,R_(C4) is H, and R_(C5) and R_(C6) are each CH₃, R_(C3) is not—CH₂—R_(C7), where R_(C7) is unsubstituted phenyl; and

where when X is CH═CH, R_(C1) and R_(C2) combine to form a (═O) group,R_(C4) is H, and R_(C5) and R_(C6) are H, R_(C3) is not—CH₂(4-halophenyl);

or any pharmaceutically acceptable salt or solvate thereof; or anystereoisomer thereof.

In some embodiments, each R_(C5) and R_(C6) is optionally substitutedC₁₋₆ alkyl.

In other embodiments, the compound has a structure according to thefollowing formula:

wherein X, R_(C1), R_(C2), R_(C3), and R_(C4) are as defined for Formula(IV) and n is an integer between 0-3,

or any pharmaceutically acceptable salt or solvate thereof; or anystereoisomer thereof.

In some embodiments, R_(C1) and R_(C2), combine to form a (═O) group.

In other embodiments, X is S.

In some embodiments, n is 1.

In certain embodiments, R_(C3) is —Y—R_(C7).

In other embodiments, R_(C3) is —(CH₂)-(optionally substituted aryl).

In a sixth aspect, the invention features a compound having a structureaccording to the following formula

where

each Y_(D1) and Y_(D2) is selected, independently, from —C(═O)— or—S(═O)₂—;

A is phenyl having 0, 1, 2, 3, or 4 additional substituents;

R_(D2) and R_(D3) are selected, independently from H, halogen, CN, NC,N₃, NO₂, —COR_(D13), —CO₂R_(D13), —CONR_(D13)R_(D14), optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

each R_(D5), R_(D9), R_(D10), R_(D13), and R_(D14) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, orR_(D9) and R_(D10) combine to form a heterocyclyl; and

where when R_(D2), R_(D3), and R_(D5) are H, Y_(D1) is —(C═O)—, Y_(D2)is —(SO₂)—, and R_(D9) and R_(D10) are each ethyl or R_(D9) is methyland R_(D10) is CH₂(2-tetrahydrofuran), and A is phenyl having 0additional substituents, Y_(D1) and Y_(D2) are not para to each other,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, Y_(D1) and Y_(D2) are ortho or meta to each other.

In other embodiments, Y_(D1) and Y_(D2) are para to each other.

In some embodiments, the compound has a structure according to thefollowing formula

where

each R_(D2), R_(D3), R_(D17), R_(D18), R_(D19), and R_(D20), isselected, independently from H, halogen, CN, NC, N₃, NO₂, —COR_(D13),—CO₂R_(D13), —CONR_(D13)R_(D14), optionally substituted C₁₋₆ alkyl,optionally substituted aryl, or optionally substituted heteroaryl; and

each R_(D9) and R_(D10) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl, oroptionally substituted aryl, or R_(D9) and R_(D10) combine to form aheterocyclyl;

or any pharmaceutically acceptable salt or solvate thereof or anystereoisomer thereof.

In some embodiments, R_(D17), R_(D18), R_(D19), and R_(D20) are H.

In some embodiments, R_(D2) and R_(D3) are H.

In other embodiments, R_(D9) and R_(D10) are each optionally substitutedC₁₋₆ alkyl.

In a seventh aspect, the invention features a compound having astructure according to

where

each Z_(E2) and Z_(E3) is selected, independently, from a single bond,—(CR_(E6)R_(E7))_(n)—, —C(═O)—, or R_(E1) and Z_(E2)—R_(E2) combine toform a double bond;

each R_(E1), R_(E2), and R_(E4) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl;

R_(E3) is selected from optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

each R_(E6) and R_(E7) is selected, independently, from H or optionallysubstituted C₁₋₆ alkyl; and

each n is an integer between 1-6; and

where when R_(E1) and R_(E4) are H, Z_(E2) and Z_(E3) are each CH₂, andR_(E2) is unsubstituted 3-indolyl, R_(E3) is not 4-chlorophenyl orCH₂CH₂O(p-C₆H₄F),

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, the compound has a structure according to

where

R_(E3) is optionally substituted aryl or optionally substitutedheteroaryl; and

R⁹ is H, halogen, CN, NO₂, OR¹³, NR¹³R¹⁴, COR¹⁵, CO₂R¹⁵, or optionallysubstituted C₁₋₆ alkyl;

each R¹³ and R¹⁴ is selected, independently, from H, COR¹⁶, CO₂R¹⁶,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; and,

each R¹⁵ and R¹⁶ is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(E3) is optionally substituted aryl.

In some embodiments, R_(E3) is unsubstituted C₃₋₁₀ cycloalkyl,unsubstituted heterocyclyl, unsubstituted aryl, or unsubstitutedheteroaryl.

In other embodiments, R_(E3) is substituted C₃₋₁₀ cycloalkyl,substituted heterocyclyl, substituted aryl, or substituted heteroaryl.In other embodiments, the substituted C₃₋₁₀ cycloalkyl, substitutedheterocyclyl, substituted aryl, or substituted heteroaryl includes 1, 2,3, 4, or 5 substituents selected, independently, from the groupconsisting of: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, —N₃, —OR′, —NR′C(═O)R″,—C(═O)NRR′, —NRR′, —OC(═O)NR′R″, —NRC(═O)OR′, —OH, and —NC), whereineach R or R′ is selected, independently, from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In still other embodiments, R_(E3) is substituted aryl or substitutedheteroaryl. In some embodiments, R_(E3) is substituted phenyl. In someembodiments, the substituted phenyl is substituted with at least onehalogen. In other embodiments, the substituted phenyl is substitutedwith 1, 2, 3, 4, or 5 substituents selected, independently, from thegroup consisting of: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, —N₃, —OR′, —NR′C(═O)R″,—C(O)NRR′, —NRR′, —OC(═O)NR′R″, —NRC(═O)OR′, —OH, and —NC), wherein eachR or R′ is selected, independently, from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, the stereocenter marked by the asterisk in thecompound of Formula (VI) has the (R)-configuration. In otherembodiments, the stereocenter marked by the asterisk has the(S)-configuration.

In any of the embodiments described herein, one or both of —Z_(E3) andR_(E3) does not include substituents selected from the group consistingof: halogen (e.g., F, Cl, Br, or I); nitro (—NO₂), cyano (—CN),acyloxy(—OC(═O)R′), acyl (—C(═O)R′), carboxylic acid (—CO₂H), carboxylicester (—CO₂R′), sulfonate (—S(═O)₂OR), sulfonamide (—S(═O)₂NRR′ or—NRS(═O)₂R′), or sulfonyl (—S(═O)₂R), where each R or R′ is selected,independently, from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl, as described herein.

In an eighth aspect, the invention features a compound having astructure according to the following formula,

where

Z_(F1) is selected from a single bond, —(CH₂)—, —C(═O)—, or —S(═O)₂—;

R_(F1) is selected from H, OR_(F14), optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl;

R_(F2) and R_(F4) are each H, or R_(F2) and R_(F4) combine to form acarbon-carbon double bond;

each R_(F6), R_(F7), R_(F8), and R_(F9) is selected, independently, fromH, halogen, CN, NC, N₃, NO₂, OR_(F12), SR_(F12), NR_(F12)R_(F13),—COR_(F12), —CO_(2 F12), —CONR_(F12)R_(F13), optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; and

each R_(F12), R_(F13), and R_(F14) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; and

where when R_(F2), R_(F4), R_(F6), R_(F7), R_(F8), and R_(F9) are each Hand Z_(F1) is —C(═O)—, R_(F1) is not -(unsubstituted 1,4-benzodioxane)or —CH₂—O-(unsubstituted phenyl), or —CH(CH₃)O(o-tolyl);

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(F2) and R_(F4) are each H.

In other embodiments, R_(F6), R_(F7), R_(F8), and R_(F9) are H.

In certain embodiments, Z_(F1) is —C(═O)—. In further embodiments,R_(F1) is optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl.

In a ninth aspect, the invention features a compound having a structureaccording to the following formula

where

each R_(G1), R_(G2), R_(G5), and R_(G6) is selected, independently, fromH, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl, or R_(G1) and R_(G2), orR_(G5) and R_(G6) combine to form an optionally substituted cycloalkylor heterocyclyl; and

where when R_(G1) is unsubstituted phenyl and R_(G2) is H, R_(G5) andR_(G6) do not combine to form unsubstituted cyclopentyl;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(G1) or R_(G5) is phenyl having 0, 1, 2, 3, 4, or5 substituents. In certain embodiments, R_(G1) is unsubstituted phenyl.

In some embodiments, R_(G2) or R_(G6) is phenyl having 0, 1, 2, 3, 4, or5 substituents.

In other embodiments, R_(G1) and R_(G2), or R_(G5) and R_(G6) combine toform an optionally substituted cycloalkyl. In certain embodiments, thecycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In a tenth aspect, the invention features a pharmaceutical compositionincluding a pharmaceutically acceptable excipient and any compound ofFormulas (I)-(VIII), or any of Compounds (1)-(7), (13)-(26), (27)-(33),(48)-(57), and (58)-(70), or any pharmaceutically acceptable salt orsolvate thereof, or stereoisomer thereof.

In an eleventh aspect, the invention features a method of treating acondition in a subject, with the method including the step ofadministering the compound of any compound of Formulas (I)-(VIII), orany of Compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), and(58)-(70), or any pharmaceutically acceptable salt or solvate thereof,or stereoisomer thereof, to said subject in a dosage sufficient todecrease necroptosis.

In some embodiments, the condition is a neurodegenerative disease of thecentral or peripheral nervous system, the result of retinal neuronalcell death, the result of cell death of cardiac muscle, the result ofcell death of cells of the immune system; stroke, liver disease,pancreatic disease, the result of cell death associated with renalfailure; heart, mesenteric, retinal, hepatic or brain ischemic injury,ischemic injury during organ storage, head trauma, septic shock,coronary heart disease, cardiomyopathy, myocardial infarction, boneavascular necrosis, sickle cell disease, muscle wasting,gastrointestinal disease, tuberculosis, diabetes, alteration of bloodvessels, muscular dystrophy, graft-versus-host disease, viral infection,Crohn's disease, ulcerative colitis, asthma, or any condition in whichalteration in cell proliferation, differentiation or intracellularsignaling is a causative factor.

In some embodiments, the condition is a neurodegenerative disease of thecentral or peripheral nervous system.

In some embodiments, the condition is hepatic or brain ischemic injury,or ischemic injury during organ storage, head trauma, septic shock, orcoronary heart disease.

In some embodiments, the condition is stroke.

In some embodiments, the condition is myocardial infarction.

In a twelfth aspect, the invention features a method of decreasingnecroptosis, where the method includes contacting a cell with anycompound of Formulas (I)-(VIII), or any of Compounds (1)-(7), (13)-(26),(27)-(33), (48)-(57), and (58)-(70)), or any pharmaceutically acceptablesalt or solvate thereof, or stereoisomer thereof.

In a thirteenth aspect, the invention features a kit including

(a) a pharmaceutical composition comprising any compound of Formulas(I)-(VIII), or any of Compounds (1)-(7), (13)-(26), (27)-(33),(48)-(57), and (58)-(70), or any pharmaceutically acceptable salt orsolvate thereof, or stereoisomer thereof; and

(b) instructions for the use of the pharmaceutical composition of (a) totreat a condition in a subject.

In any of the compositions, methods, and kits of the invention, thecompound can be selected from the group consisting of:

or any pharmaceutically acceptable salt or solvate thereof, orstereoisomer thereof.

By “C₁₋₄ alkaryl” is meant a C₁₋₄ alkyl group having an optionallysubstituted aryl or an optionally substituted heteroaryl located at anyposition of the carbon chain. The C₁₋₄ alkyl group may be linear orbranched and may also be substituted with, for example, 1, 2, 3, 4, or 5additional substituents as described herein.

By “alkoxy” is meant a group having the structure —O(optionallysubstituted C₁₋₆ alkyl), where the optionally substituted C₁₋₆ alkyl maybe branched, linear, or cyclic. The C₁₋₆ alkyl may be substituted orunsubstituted. A substituted C₁₋₆ alkyl can have, for example, 1, 2, 3,4, 5, or 6 substituents located at any position. Exemplary alkoxy groupsinclude, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy,tert-butoxy, and the like.

By “C₂₋₆ alkenyl” or “alkenyl” is meant an optionally substitutedunsaturated C₂₋₆ hydrocarbon group having one or more carbon-carbondouble bonds. Exemplary C₂₋₆ alkenyl groups include, but are not limitedto —CH═CH (ethenyl), propenyl, 2-propenyl, 2-methyl-1-propenyl,1-butenyl, 2-butenyl, and the like. A C₂₋₆ alkenyl may be linear orbranched and may be unsubstituted or substituted. A substituted C₂₋₆alkenyl may have, for example, 1, 2, 3, 4, 5, or 6 substituents locatedat any position.

By “C₁₋₆ alkyl” or “alkyl” is meant an optionally substituted C₁₋₆saturated hydrocarbon group. An alkyl group may be linear, branched, orcyclic (“cycloalkyl”). Examples of alkyl radicals include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl,n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, andthe like, which may bear one or more sustitutents. Substituted alkylgroups may have, for example, 1, 2, 3, 4, 5, or 6 substitutents locatedat any position. Exemplary substituted alkyl groups include, but are notlimited to, optionally substituted C₁₋₄ alkaryl groups.

By “C₂₋₆ alkynyl” or “alkynyl” is meant an optionally substitutedunsaturated C₂₋₆ hydrocarbon group having one or more carbon-carbontriple bonds. Exemplary C₂₋₆ alkynyl groups include, but are not limitedto ethynyl, 1-propynyl, and the like

By “amino” is meant a group having a structure —NR′R″, where each R′ andR″ is selected, independently, from H, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, or R′ and R″ combine to form an optionally substitutedheterocyclyl. When R′ is not H or R″ is not H, R′ and R″ may beunsubstituted or substituted with, for example, 1, 2, 3, 4, 5, or 6substituents.

By “aryl” is meant is an optionally substituted C₆-C₁₄ cyclic group with[4n+2] π electrons in conjugation and where n is 1, 2, or 3.Non-limiting examples of aryls include heteroaryls and, for example,benzene, naphthalene, anthracene, and phenanthrene. Aryls also includebi- and tri-cyclic ring systems in which a non-aromatic saturated orpartially unsaturated carbocyclic ring (e.g., a cycloalkyl orcycloalkenyl) is fused to an aromatic ring such as benzene ornapthalene. Exemplary aryls fused to a non-aromatic ring includeindanyl, tetrahydronaphthyl. Any aryls as defined herein may beunsubstituted or substituted. A substituted aryl may be optionallysubstituted with, for example, 1, 2, 3, 4, 5, or 6 substituents locatedat any position of the ring.

By “aryloxy” is meant a group having the structure —O(optionallysubstituted aryl), where aryl is as defined herein.

By “azido” is meant a group having the structure —N₃.

By “carbamate” or “carbamoyl” is meant a group having the structure—OCONR′R″ or —NR′CO₂R″, where each R′ and R″ is selected, independently,from H, optionally substituted C₁₋₆ alkyl, optionally substitutedcycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, or R′ and R″ combine to form anoptionally substituted heterocyclyl. When R′ is not H or R″ is not H, R′and R″ may be unsubstituted or substituted with, for example, 1, 2, 3,4, 5, or 6 substituents.

By “carbonate” is meant a group having a the structure —OCO₂R′, where R′is selected from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl. When R′ is notH, R may be unsubstituted or substituted with, for example, 1, 2, 3, 4,5, or 6 substituents.

By “carboxamido” or “amido” is meant a group having the structure—CONR′R″ or —NR′C(═O)R″, where each R′ and R″ is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, or R′ and R″combine to form an optionally substituted heterocyclyl. When R′ is not Hor R″ is not H, R′ and R″ may be unsubstituted or substituted with, forexample, 1, 2, 3, 4, 5, or 6 substituents.

By “carboxylic group” is meant a group having the structure —CO₂R′,where R′ is selected from H, optionally substituted C₁₋₆ alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl. WhenR′ is not H, R may be unsubstituted or substituted with, for example, 1,2, 3, 4, 5, or 6 substituents.

By “cyano” is meant a group having the structure —CN.

By “C₃₋₁₀ cycloalkyl” or “cycloalkyl” is meant an optionallysubstituted, saturated or partially unsaturated 3- to 10-memberedmonocyclic or polycyclic (e.g., bicyclic, or tricyclic) hydrocarbon ringsystem. Where a cycloalkyl is polycyclic, the constituent cycloalkylrings may be fused together, form a spirocyclic structure, or thepolycyclic cycloalkyl may be a bridged cycloalkyl (e.g., adamantyl ornorbonanyl). Exemplary cycloalkyls incluce cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyls may beunsubstituted or substituted. A substituted cycloalkyl can have, forexample, 1, 2, 3, 4, 5, or 6 substituents.

By “cycloalkenyl” is meant a non-aromatic, optionally substituted 3- to10-membered monocyclic or bicyclic hydrocarbon ring system having atleast one carbon-carbon double bound. For example, a cycloalkenyl mayhave 1 or 2 carbon-carbon double bonds. Cycloalkenyls may beunsubstituted or substituted. A substituted cycloalkenyl can have, forexample, 1, 2, 3, 4, 5, or 6 substituents. Exemplary cycloalkenylsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl,1,4-cyclohexadienyl, and the like.

By “effective amount” or “therapeutically effective amount” of an agent,as used herein, is that amount sufficient to effect beneficial ordesired results, such as clinical results, and, as such, an effectiveamount depends upon the context in which it is being applied. Forexample, in the context of administering an agent that is an inhibitorof necroptosis, an effective amount of an agent is, for example, anamount sufficient to achieve a reduction in necroptosis as compared tothe response obtained without administration of the agent.

By “ester” is meant a group having a structure selected from —OCOR′,where R′ is selected from H, optionally substituted C₁₋₆ alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl. WhenR′ is not H, R may be unsubstituted or substituted with, for example, 1,2, 3, 4, 5, or 6 substituents.

By “halogen” or “halo” is meant fluorine (—F), chlorine (—Cl), bromine(—Br), or iodine (—I).

By “heteroaryl” is mean an aryl group that contains 1, 2, or 3heteroatoms in the cyclic framework. Exemplary heteroaryls include, butare not limited to, furan, thiophene, pyrrole, thiadiazole (e.g.,1,2,3-thiadiazole or 1,2,4-thiadiazole), oxadiazole (e.g.,1,2,3-oxadiazole or 1,2,5-oxadiazole), oxazole, benzoxazole, isoxazole,isothiazole, pyrazole, thiazole, benzthiazole, triazole (e.g.,1,2,4-triazole or 1,2,3-triazole), benzotriazole, pyridines,pyrimidines, pyrazines, quinoline, isoquinoline, purine, pyrazine,pteridine, triazine (e.g, 1,2,3-triazine, 1,2,4-triazine, or1,3,5-triazine)indoles, 1,2,4,5-tetrazine, benzo[b]thiophene,benzo[c]thiophene, benzofuran, isobenzofuran, and benzimidazole.Heteroaryls may be unsubstituted or substituted. Substituted heteroarylscan have, for example, 1, 2, 3, 4, 5, or 6 substitutents.

By “heterocyclic” or “heterocyclyl” is meant an optionally substitutednon-aromatic, partially unsaturated or fully saturated, 3- to10-membered ring system, which includes single rings of 3 to 8 atoms insize, and polycyclic ring systems (e.g., bi- and tri-cyclic ringsystems) which may include an aryl (e.g., phenyl or naphthyl) orheteroaryl group that is fused to a non-aromatic ring (e.g., cycloalkyl,cycloalkenyl, or heterocyclyl), where the ring system contains at leastone heterotom. Heterocyclic rings include those having from one to threeheteroatoms independently selected from oxygen, sulfur, and nitrogen, inwhich the nitrogen and sulfur heteroatoms may optionally be oxidized andthe nitrogen heteroatom may optionally be quaternized or substituted. Incertain embodiments, the term heterocylic refers to a non-aromatic 5-,6-, or 7-membered monocyclic ring wherein at least one ring atom is aheteroatom selected from O, S, and N (wherein the nitrogen and sulfurheteroatoms may be optionally oxidized), and the remaining ring atomsare carbon, the radical being joined to the rest of the molecule via anyof the ring atoms. Where a heterocycle is polycyclic, the constituentrings may be fused together, form a spirocyclic structure, or thepolycyclic heterocycle may be a bridged heterocycle (e.g., quinuclidylor. Exemplary heterocyclics include, but are not limited to, aziridinyl,azetindinyl, 1,3-diazatidinyl, pyrrolidinyl, piperidinyl, piperazinyl,thiranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl,tetrahydrothiopyranyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, pyranonyl, 3,4-dihydro-2H-pyranyl, chromenyl,2H-chromen-2-onyl, chromanyl, dioxanyl (e.g., 1,3-dioxanyl or1,4-dioxanyl), 1,4-benzodioxanyl, oxazinyl, oxathiolanyl, morpholinyl,thiomorpholinyl, thioxanyl, quinuclidinyl, and also derivatives of saidexemplary heterocyclics where the heterocyclic is fused to an aryl(e.g., a benzene ring) or a heteroaryl (e.g., a pyridine or pyrimidine)group. Any of the heterocyclic groups described herein may beunsubstituted or substituted. A substituted heterocycle may have, forexample, 1, 2, 3, 4, 5, or 6 substituents.

By “ketone” or “acyl” is meant a group having the structure —COR′, whereR′ is selected from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl. When R′ is notH, R may be unsubstituted or substituted with, for example, 1, 2, 3, 4,5, or 6 substituents.

By “nitro” is meant a group having the structure —NO₂.

A “pharmaceutically acceptable excipient” as used herein refers anyingredient other than the compounds described herein (for example, avehicle capable of suspending or dissolving the active compound) andhaving the properties of being nontoxic and non-inflammatory in apatient. Excipients may include, for example: antiadherents,antioxidants, binders, coatings, compression aids, disintegrants, dyes(colors), emollients, emulsifiers, fillers (diluents), film formers orcoatings, flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, or waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, croscarmellose,crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine,ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol,methionine, methylcellulose, methyl paraben, microcrystalline cellulose,polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinizedstarch, propyl paraben, retinyl palmitate, shellac, silicon dioxide,sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate,sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc,titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The term “pharmaceutically acceptable salt,” as used herein, representsthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66:1-19. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting the free base group with a suitableorganic acid. Representative acid addition salts include acetate,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate,hexanoate, hydrobromide, hydrochloride, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium and the like, as well as nontoxicammonium, quaternary ammonium, and amine cations, including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamineand the like.

The term “pharmaceutically acceptable solvates,” as used herein, refersto compounds that retain non-covalent associations to residual solventmolecules in the solid state. For example, solvates may be prepared bycrystallization, recrystallization, or precipitation from a solutionthat includes organic solvents, water, or a mixture thereof. Solvatesinclude, but are not limited to, compounds that include solventmolecules in the crystal lattice following recrystallization. Themolecular stoichiometry of solvation can vary from, for example, 1:1solvent:compound to 10:1 solvent:compound. These ratios can include amixture of associated solvent molecules. Exemplary, non-limitingexamples of solvents that can form solvates with the compounds of theinvention include water (for example, mono-, di-, and tri-hydrates),N-methylpyrrolidinonc (NMP), dimethyl sulfoxide (DMSO),N,N′-dimethylformamide (DMF), N,N′-dimethylacetamide (DMAC),1,3-dimethyl-2-imidazolidinone (DMEU),1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile(ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone,benzyl benzoate, or any combination thereof.

By “pharmaceutical composition” is meant a composition containing acompound of the invention, formulated with a pharmaceutically acceptableexcipient, and manufactured or sold with the approval of a governmentalregulatory agency as part of a therapeutic regimen for the treatment ofdisease in a mammal. Excipients consisting of DMSO are specificallyexcluded. Pharmaceutical compositions can be formulated, for example,for oral administration in unit dosage form (e.g., a tablet, capsule,caplet, gelcap, or syrup); for topical administration (e.g., as a cream,gel, lotion, or ointment); for intravenous administration (e.g., as asterile solution free of particulate emboli and in a solvent systemsuitable for intravenous use); or any other formulation describedherein.

By “stereoisomer” is meant a diastereomer, enantiomer, or epimer of acompound. A chiral center in a compound may have the S-configuration orthe R-configuration. Enantiomers may also be described by the directionin which they rotate polarized light (i.e., (+) or (−)). Diastereomersof a compound include stereoisomers in which some, but not all, of thechiral centers have the opposite configuration as well as thosecompounds in which substituents are differently oriented in space (forexample, trans versus cis).

Where a group is substituted, the group may be substituted with 1, 2, 3,4, 5, or 6 substituents. Optional substituents include, but are notlimited to: C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl,cycloalkenyl, heterocyclyl, aryl, heteroaryl, halogen; azido(—N₃), nitro(—NO₂), cyano (—CN), acyloxy(—OC(═O)R′), acyl (—C(═O)R′), alkoxy (—OR′),amido (—NR′C(═O)R″ or —C(═O)NRR′), amino (—NRR′), carboxylic acid(—CO₂H), carboxylic ester (—CO₂R′), carbamoyl (—OC(═O)NR′R″ or—NRC(═O)OR′), hydroxy (—OH), isocyano (—NC), sulfonate (—S(═O)₂OR),sulfonamide (—S(═O)₂NRR′ or —NRS(═O)₂R′), or sulfonyl (—S(═O)₂R), whereeach R or R′ is selected, independently, from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Asubstituted group may have, for example, 1, 2, 3, 4, 5, 6, 7, 8, or 9substituents. In some embodiments, each hydrogen in a group may bereplaced by a substituent group (e.g., perhaloalkyl groups such as CF₃or —CF₂CF₃ or perhaloaryls such as —C₆F₅). In other embodiments, asubstitutent group may itself be further substituted by replacing ahydrogen of said substituent group with another substituent group suchas those described herein. Substituents may be further substituted with,for example, 1, 2, 3, 4, 5, or 6 substituents as defined herein. Forexample, a lower C₁₋₆ alkyl or an aryl substituent group (e.g.,heteroaryl, phenyl, or naphthyl) may be further substituted with 1, 2,3, 4, 5, or 6 substituents as described herein.

DETAILED DESCRIPTION OF THE INVENTION

We have discovered a series of heterocyclic derivatives that inhibittumor necrosis factor alpha (TNF-α)-induced necroptosis. Theheterocyclic compounds of the invention include, for example, compoundsof Formulas (I)-(VIII), or any pharmaceutically acceptable salt orsolvate thereof, or any stereoisomer thereof, and are shown to inhibitTNF-α induced necroptosis in FADD-deficient variant of human Jurkat Tcells. Still other useful necrostatins include Compounds (1)-(45).Compounds of the invention can be synthesized according to methods knownin the art or by the methods provided in the examples below.Pharmaceutical compositions including the compounds of the invention arealso described. The invention also features kits and methods oftreatment featuring the compounds and compositions of the invention.

Compounds of Formula (I)

Certain compounds of the invention can be described by Formula (I):

where

each X_(H1) and X_(H2) is selected, independently, from O, S, orNR_(H9);

Y_(H1) is selected, independently, from O, S, or NR_(H10);

each R_(H1), R_(H2), R_(H3), R_(H4), R_(H5), R_(H6), R_(H7), and R_(H8),is selected, independently from H, halogen, cyano, nitro, azido,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆ alkenyl,optionally substituted C₂₋₆ alkynyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted aryl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, —C(═O)R_(H12),—C(═O)OR_(H12), —C(═O)NR_(H12)R_(H13), —C(═S)R_(H12),—C(═S)NR_(H12)R_(H13), —C(═NR_(H14))R_(H12),—C(═NR_(H14))NR_(H12)R_(H13), or—[Z_(H1)—(CR_(H15)R_(H16))_(n)-{C(═X_(H2))}_(o)—Z_(H2)—R_(H17)], orR_(H1) and R_(H3), or R_(H5) and R_(H7) combine to form a carbon-carbondouble bond;

each Z_(H1) and Z_(H2) is selected, independently, from a single bond,O, S, or NR_(H11);

each R_(H9), R_(H10), R_(H11), R_(H12), R_(H13), R_(H14), R_(H15),R_(H16), and R_(H17), is selected, independently from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl, oroptionally substituted heteroaryl;

n is an integer between 0-6; and

o is 0 or 1;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

Certain compounds of the invention can be described by Formula (I-A):

where each R_(H1), R_(H2), R_(H3), R_(H4), R_(H5), R_(H10), R_(H17),X_(H2), Z_(H1), Z_(H2), and n is as defined for Formula (I),

or by Formula (I-B)

where

each R_(H1) and R_(H3) is selected, independently, from H, halogen,cyano, nitro, azido, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted aryl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl,—C(═O)R_(H12), —C(═O)OR_(H12), or —C(═O)NR_(H12)R_(H13), or R_(H1) andR_(H3) combine to form a carbon-carbon double bond;

each R_(H4) and R_(H17) is selected, independently, from optionallysubstituted aryl or optionally substituted heteroaryl;

R_(H5) is selected from H, CN, —C(═O)OR_(H12), or —C(═O)NR_(H12)R_(H13);

each R_(H10), R_(H11), R_(H12), and R_(H13) is selected from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted aryl, optionally substitutedheterocyclyl, or optionally substituted heteroaryl;

Z_(H1) is selected from a single bond or S;

Z_(H2) is selected from a single bond or NR_(H11); and

X_(H2) is O or S;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (I), the compound has a structureaccording to the following formula:

where R_(H4) is as according to Formula (I-A) or (I-B).

In some embodiments of Formula (I), when R_(H1) is H, R_(H2) is H orCO₂Me, R_(H3) is H, R_(H4) is unsubstituted phenyl or phenyl substitutedwith 1, 2, or 3 substituents selected from methoxy, ethoxy, methyl,isopropyl, chloro, or fluoro, R_(H5) is CN, R_(H6) and R_(H8) is H,R_(H10) is H, X_(H1) is O, Y_(H1) is NH, and R_(H7) is—[S—(CH₂)—{C(═O)}_(o)—Z_(H2)—R₁₇], Z_(H2)—R_(F17) is not OCH₃ orNH—R_(H17), where R_(H17) is H, unsubstituted 2-thiazolyl, unsubstitutedphenyl, 4-methoxyphenyl, 4-fluorophenyl, or 2,4,6-trimethylphenyl.

Compounds of Formulas (I), (I-A), (I-B), and (I-C) can be preparedaccording to methods known in the art. An exemplary method of synthesisthat can be used is shown in Scheme 1 and is based on protocolsdisclosed in Russian Chemical Bulletin, 48(12): 2308-2311 (1999) and inChemistry of Heterocyclic Compounds, 38(10): 1269-1275 (2002). In Scheme1, R′ and R″ can be, for example, an optionally substituted aryl or anoptionally substituted heteroaryl group. Still other substituentpatterns can be obtained by variation of the thioamide starting materialthat is condensed with the aldehyde.

Compounds of Formula (I) (e.g., (I-A), (I-B), or (I-C)) or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof, can also be used as described herein (e.g., in pharmaceuticalcompositions, as inhibitors of necroptosis, in methods of treatment, andin kits). Exemplary compounds useful in the methods, compositions, andkits of the invention, include but are not limited to those shown inTable 1. Other compounds of Formula I are shown in Table 2. In someembodiments, Formulas (I), (I-A), (I-B), or (I-C) do not include any ofCompounds (1)-(12).

TABLE 1 Com- pound Structure (1)

(2)

(3)

(4)

(5)

(6)

(7)

TABLE 2 (8)

(9)

(10)

(11)

(12)

Compounds of Formula (II)

Select compounds of the invention can be described by Formula (II)

where

each R_(A1), R_(A2), R_(A3), R_(A4), R_(A5), and R_(A6) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, or a group having the structure—X_(A1)-G_(A1)-X_(A2)—C(═Y_(A1))-G_(A2)-X_(A3)—R_(A7), or R_(A1) andR_(A4) combine to form a carbon-carbon double bond;

each X_(A1), X_(A2), and X_(A3) is, independently, absent or selectedfrom —O—, —S—, or —NR_(A8)—;

G_(A1) is absent or —(CR_(A9)R_(A10))_(m)—;

G_(A2) is absent or —(CR_(A11)R_(A12))_(n)—;

Y_(A1) is O, S, or NR_(A13);

each R_(A8) and R_(A13) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —COR_(A14), —CO₂R_(A14), or—CONR_(A14)R_(A15);

each R_(A9), R_(A10), R_(A11), and R_(A12) is selected, independently,from H, halogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

each R_(A7), R_(A14) and R_(A15) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl; and

each m and n is, independently, 1, 2, or 3;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (II), when R_(A1) and R_(A4) combine toform a carbon-carbon double bond, R_(A2) is H, R_(A3) is CH₃, and R_(A6)is CO₂H, R_(A5) is not CH₂(2-chlorophenyl).

In some embodiments of Formula (II), when R_(A1) and R_(A4) combine toform a carbon-carbon double bond, R_(A2) is H, R_(A6) is CH₃ or ^(t)Bu,and R_(A3) is NHC(═O)NHR_(A7), R_(A7) is not chlorophenyl ordichlorophenyl.

Certain compounds of Formula (II) may be described further according toFormula (II-A)

where

each R_(A1), R_(A3), R_(A4), and R_(A7) is selected, independently, fromH, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl, or R_(A1) and R_(A4) combineto form a carbon-carbon double bond;

G_(A2) is absent or is —(CR_(A11)R_(A12))_(n)—;

X_(A3) is absent or is O, S, or NR_(A8);

each R_(A11), R_(A12), and R_(A8) is selected, independently, from H oroptionally substituted C₁₋₆ alkyl; and

n is 1 or 2;

or according to Formula (II-B)

where

R_(A5) is H;

each R_(A1), R_(A2), R_(A3), R_(A4), and R_(A6) is selected,independently, from H, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)—X_(A3)—R_(A7), or R_(A1) and R_(A4)combine to form a carbon-carbon double bond;

each R_(A7) is selected, independently, from H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

each X_(A3) is, independently, absent, —O—, or —NR_(A8)—,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (II) (e.g., (II-A) and (II-B)), when oneof R_(A1) and R_(A4) is H and the other is selected from H or CO₂Et, andR_(A3) is unsubstituted phenyl, G_(A2)-X_(A3)—R_(A7) is not NHC₆H₅,NH(p-C₆H₄F), NH(p-C₆H₄OH), NH(p-C₆H₄OMe), NH(3-OH-4-Cl—C₆H₄),—CH₂(O-p-C₆H₄Me), —CH₂(4-ethylpiperazinyl), —CH₂S(2-phenyltetrazolyl),—CH₂S(4-chlorophenyl), —CH₂S(2-benzothiazolyl),—CH₂S(2-(N-methylimidazolyl)), —CH₂S(4,6-dimethylquinazolinyl),adamantyl, or optionally substituted oxiranyl.

Other compounds of Formula (II) include compounds of Formula (II-C):

where

each R_(A1), R_(A2), R_(A4), and R_(A6) is selected, independently, fromH, —C(═O)—X_(A3)—R_(A7), optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl, or R_(A1) and R_(A4) combine to form a carbon-carbon doublebond;

each X_(A3) is, independently, absent, —O—, or —NR_(A8)—,

each R_(A8) is selected, independently, from H, optionally substitutedC₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —COR_(A14), —CO₂R_(A14), or —CONR_(A14)R_(A15);and

each R_(A7), R_(A14) and R_(A15) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl.

In some embodiments of Formula (II-C), wherein when R_(A1) and R_(A4)combine to form a carbon-carbon double bond and R_(A2) is H, R_(A6) isnot 4-chlorophenyl, 4-methoxyphenyl, or 4-(NHCO₂ ^(t)Bu)phenyl. In otherembodiments, when R_(A1) is H, R_(A4) is H or CO₂Et, R_(A2) isunsubstituted phenyl, R_(A6) is not —C(═O)-(unsubstituted phenyl) or—C(═O)-(4-methylphenyl). In still other embodiments, when R_(A1) is H,R_(A4) is —C(═O)-(unsubstituted phenyl), R_(A2) is 4-chlorophenyl,R_(A6) is not CO₂Et.

Compounds of Formula (II) (e.g., (II-A)-(II-C)) can be preparedaccording to methods known in the art. Exemplary methods of synthesisare shown in Schemes 2-5.

Scheme 2A shows a method that can be used to prepare pyrazole compoundsof Formula (II). Terminal alkynes can be reacted withtrimethylsilyldiazomethane (TMS-diazomethane) to afford compounds ofFormula (II) where R_(A1) and R_(A4) combine to form a carbon-carbondouble bond and R′ can be, for example, optionally substituted aryl oroptionally substituted heteroaryl. Scheme 2B shows the preparation ofCompound (13) using the method in Scheme 2A in which the aniline —NH₂group is protected prior to the reaction with TMS-diazomethane.

Scheme 3A depicts another method that can be used to synthesizepyrazoline compounds of Formula (II) according to methods described inJ. Chem. Soc. 4686-90 (1952) and J. Med. Chem. 2127-2137 (2006). Forexample, substituted acroleins (e.g., R′ can be optionally substitutedaryl or optionally substituted heteroaryl) can be treated with ethanolichydrazine (Step (a)) to afford a pyrazoline intermediate. The pyrazolinecan then be treated with an electrophilic compound having a suitableleaving group (e.g., alkyl halides, acid cholorides. or acid anhydrides)and an optional chemical promotoer to afford N-substituted pyrazolines.Scheme 3B shows a method that can be used to prepare Compound (14) wherean acid chloride can be used in Step (b) as shown.

Scheme 4 shows Compound (15) which can be prepared according to theprocedure described in J. Am. Chem. Soc., page 165 (1943). This methodcan also be used to prepare other pyrazoline compounds of Formula (II),where R_(A6) is —C(═O)—R_(A7) and R_(A2) and R_(A7) are, independently,optionally substituted aryl or optionally substituted heteroaryl.

Scheme 5A depicts a method by which tetrazole compounds of Formula (II)can be prepared using methods described in WO2005115147 and in J. Med.Chem., 4686-90 (1952). For example, a tetrazole compound that includes acarboxylic acid group can be activated (e.g., treatment with PCl₅ as inStep (a)) and subsequently treated with a nucleophile R″ as in Step (b).Scheme 5B shows that 5-Phenyl-4,5-dihydro-1H-pyrazole can be used as thenucleophile in step (b′) to afford Compound (16).

Compounds of Formula (II) (e.g., (II-A) and (II-B) and compounds(13)-(16)), or any pharmaceutically acceptable salt or solvate thereof,or any stereoisomer thereof, can also be used as described herein (e.g.,in pharmaceutical compositions, as inhibitors of necroptosis, in methodsof treatment, and in kits). Additional exemplary compounds useful in,for example, the methods, compositions, and kits of the invention,include but are not limited to those shown in Table 3. Other compoundsof Formula (II) are shown in Table 4. In some embodiments, Formula (II),(II-A), and (II-B) do not include any of compounds (13)-(26).

TABLE 3 Compound Structure (17)

(18)

(19)

(20)

(21)

TABLE 4 Compound Structure (22)

(23)

(24)

(25)

(26)

Compounds of Formula (III)

Select compounds of the invention can be described by Formula (III)

where

R_(B1) is selected from H, optionally substituted C₁₋₆ alkyl,—C(═O)R_(B18), —C(═O)OR_(B18), or —C(═O)NR_(B18)R_(B19);

R_(B2) is selected from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, or optionally substituted C₂₋₆ alkynyl;

each R_(B3) and R_(B4) is selected, independently from H, optionallysubstituted C₁₋₆ alkyl, or R_(B3) and R_(B4) combine to form a bridginggroup having the structure—(CH₂)_(n)—(CR_(B13)═CR_(B14))_(o)—(CH₂)_(p)—;

each n, o, and p is, independently, 0 or 1;

each R_(B5), R_(B6), R_(B7), R_(B8), R_(B9), R_(B10), R_(B11), andR_(B12) is selected, independently, from H, halogen, —CN, —NO₂, —N₃,—R_(B13), —OR_(B13), —SR_(B13), —NR_(B13)R_(B14), —C(═O)R_(B15),—C(═O)OR_(B15), —C(═O)NR_(B15)R_(B16), —OC(═O)R_(B15), —OC(═O)OR_(B15),—OC(═O)NR_(B15)R_(B16), —NR_(B15)C(═O)R_(B15), —NR_(B15)C(═O)OR_(B16),—NR_(B15)C(═O)NR_(B16)R_(B17), —C(═S)R_(B15), —C(═S)NR_(B15)R_(B16),—NR_(B15)C(═S)R_(B16), —NR_(B15)C(═S)NR_(B16)R_(B17),—C(═NR_(B13))NR_(B15)R_(B16), —NR_(B15)C(═NR_(B13))R_(B16),—NR_(B15)C(═NR_(B13))NR_(B16)R_(B17);

each R_(B13) and R_(B14) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,—C(═O)OR_(B18), or —C(═O)NR_(B18)R_(B19);

each R_(B15), R_(B16), R_(B17), R_(B18), and R_(B19) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; and

where when each n, o, and p is 0, R_(B3) and R_(B4) combine to form asingle bond,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

Select compounds of Formula (III) can also be described by Formula(III-A)

where R_(B1) is as described in Formula (III), R_(B2) is ethyl, ethenyl,or ethynyl and each R_(B9), R_(B10), R_(B11), and R_(B12) is selected,independently, from H and halogen,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(B1) is H.

Still other compounds of Formula (III) are described by Formula (III-B)

where R_(BI) is as described in Formula (III), R_(B2) is ethyl, ethenyl,or ethynyl and each R_(B9), R_(B10), R_(B11), and R_(B12) is selected,independently, from H and halogen,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, R_(B1) is H.

In some embodiments of Formula (III), R_(B1) is not H or CH₃ whenR_(B5), R_(B6), R_(B7), R_(B8), R_(B9), R_(B10), R_(B11), and R_(B12)are each H, R_(B2) is ethyl, ethenyl, ethynyl, propynyl, 2-haloethynyl,—(C≡CC(—OH)(CH₃)₂), and when R_(B3) and R_(B4) are each H or combine toform a bond, —CH₂CH₂— or —CH═CH—. In other embodiments of Formula (III),R_(B1) is not H when R_(B5), R_(B6), R_(B7), R_(B8), R_(B10), andR_(B11) are each H, at least one of R_(B9) or R_(B12) is fluoro, R_(B2)is ethynyl, and when R_(B3) and R_(B4) combine to form —CH₂CH₂—. Instill other embodiments of Formula (III), R_(B1) is not H when R_(B6),R_(B7), R_(B8), R_(B10), and R_(B11) are H and one or two of R_(B6),R_(B8), R_(B10), and R_(B12) is halogen, nitro, or methyl.

Scheme 6A depicts a method by which compounds of Formula (III) can beprepared. A ketone derivative can be treated with an anionic carbonnucleophile (e.g., lithium trimethylsilylacetylide formed in step (a)).The resulting alkoxide can be trapped using a protic quench or by theaddition of an electrophilic reagent. Finally, the trimethylsilyl groupcan be deprotected using basic conditions. If desired, the alkyne groupcan be further manipulated (e.g., subjected to hydrogenation conditionsto afford the corresponding alkene or alkyl group or treated with ametal catalyst/and organic electrophile in cross-coupling reactions).Scheme 6B shows Compound (27), which can be prepared using theseconditions.

Compounds of Formula (III) (e.g., (III-A) and (III-B) and compound(27)), or any pharmaceutically acceptable salt or solvate thereof, orany stereoisomer thereof, can also be used as described herein (e.g., inpharmaceutical compositions, as inhibitors of necroptosis, in methods oftreatment, and in kits). Additional exemplary compounds useful in, forexample, the methods, compositions, and kits of the invention, includebut are not limited to those shown in Table 5. Other compounds ofFormula (III) include Compounds (35)-(36), (39)-(40), and (42)-(47)shown in Table 6. In some embodiments, Formula (III) does not includeany of Compounds (27)-(33), (35)-(36), (39)-(40), or (42)-(47).

TABLE 5 Compound Structure (28)

(29)

(30)

(31)

(32)

(33)

TABLE 6 Compound Structure (34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

Compounds of Formula (IV)

Still other compounds can be described according to Formula (IV)

where

each R_(C1), R_(C2), and R_(o) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, —Y—R_(C7), or R_(C1) and R_(C2)combine to form a (═O) or a (═S) group, or R_(C1) and R_(C3) combine toform a carbon-nitrogen double bond;

R_(C4) is selected from H, halogen, —CN, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, optionally substitutedheteroaryl, or —C(═O)ZR_(C8),

each R_(C5) and R_(C6) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, or R_(C1) and R_(C2) combine to form anoptionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

each R_(C7), R_(C8), R_(C9), R_(C10), R_(C11), and R_(C12) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl;

X is —CR_(C11)—CR_(C12)—, O, S, or NR_(C9);

Y is, independently, a single bond, (CR_(C8)R_(C9))_(n), O, S, orNR_(C10);

Z is a single bond, O, S, or NR_(C10);

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (IV), when X is S, R_(C1) and R_(C2)combine to form a (═O) group, R_(C4) is H, and R_(C5) and R_(C6) combineto form unsubstituted cyclopentyl, R_(C3) is not —CH₂—R_(C7), whereR_(C7) is unsubstituted phenyl, unsubstituted naphthyl, unsubstituted8-quinolyl, unsubstituted 2-oxoquinolyl, or phenyl having 1 or 2substituents selected from F, OMe, Me, CN, or Cl. In other embodimentsof Formula (IV), when X is S, R_(C1) and R_(C2) combine to form a (═O)group, R_(C4) is H, and R_(C5) and R_(C6) are each Me, R_(C3) is not—CH₂—R_(C7), where R_(C7) is unsubstituted phenyl. In other embodimentsof Formula (IV), when X is CH═CH, R_(C1) and R_(C2) combine to form a(═O) group, R_(C4), R_(C5) and R_(C6) are H, R_(C3) is not—CH₂(4-halophenyl).

Select compounds of Formula (IV) can also be described by Formula (IV-A)

where X, R_(C1), R_(C2), R_(C3), and R_(C4) are as defined for Formula(IV) and n is an integer between 0-3,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

Scheme 7A depicts a method by which compounds of Formula (IV) (e.g.,compounds of Formula (IV-A)) can be prepared. A heterocyclic derivativecan be deprotonated using a base such as NaH and subsequently treatedwith an electrophile (e.g., an alkyl halide such as benzyl bromide, anacid chloride, or an acid anhydride) to afford a compound of Formula(IV) such as Compound (48) shown in Scheme 7B.

Compounds of Formula (IV) (e.g., (IV-A) and Compound (48)), or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof, can also be used as described herein (e.g., in pharmaceuticalcompositions, as inhibitors of necroptosis, in methods of treatment, andin kits). Additional exemplary compounds useful in, for example, themethods, compositions, and kits of the invention, include but are notlimited to those shown in Table 7. In some embodiments, Formula (IV)does not include any of Compounds (48)-(57).

TABLE 7 Compound Structure (49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

Compounds of Formula (V)

Other compounds of the invention can be described by Formula (V)

where

each X_(D1) and X_(D2) is selected, independently, from O, S, NR_(D5),or CR_(D6)R_(D7);

Y_(D1) is selected from a covalent bond, —C(═O)—, —S(═O)—, or —S(═O)₂—;

Y_(D2) is selected from a covalent bond, —C(═O)—, —OC(═O)—,—NR_(D8)C(═O)—, —S(═O)—, —S(═O)₂—, —OS(═O)—, —OS(═O)₂—, —NR_(D8)S(═O)—,—NR_(D8)S(═O)₂—, or —C(═S)—;

A is selected from optionally substituted aryl or optionally substitutedheteroaryl;

G_(D1) is selected from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl, OR_(D9),or NR_(D9)R_(D10);

each R_(D1), R_(D2), R_(D3), R_(D4), R_(D6), R_(D7), is selected,independently, from H, halogen, CN, NC, N₃, NO₂, OR_(D11), SR_(D11),NR_(D11)R_(D12), —COR_(D13), —CO₂R_(D13), —CONR_(D13)R_(D14), optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl, or R_(D1) and R_(D4), or R_(D1) andR_(D5), or R_(D1) and R_(D6), or R_(D3) and R_(D5), or R_(D3) and R_(D6)combine to form a double bond;

each R_(D5), R_(D8), R_(D9), R_(D10), R_(D13), R_(D14), R_(D15), andR_(D16) is selected, independently, from H, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl, or R_(D9) and R_(D10) combine to form a heterocyclyl;

each R_(D11) and R_(D12) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —COR_(D15), —CO₂R_(D15),—CONR_(D15)R_(D16), —S(═O)R_(D15), —S(═O)OR_(D15),—S(═O)NR_(D15)R_(D16), —S(═O)₂R_(D15), —S(═O)₂OR_(D15),—S(═O)₂NR_(D15)R_(D16);

where Y_(D1) and Y_(D2) are each covalently bound to a carbon center inA;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

Still other compounds of Formula (V) can be described by Formula (V-A)

where

each Y_(D1) and Y_(D2) is selected, independently, from —C(═O)— or—S(═O)₂—;

A is phenyl having 0, 1, 2, 3, or 4 additional substituents;

R_(D2) and R_(D3) are selected, independently from H, halogen, CN, NC,N₃, NO₂, —COR_(D13), —CO₂R_(D13), —CONR_(D13)R_(D14), optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

each R_(D5); R_(D9), R_(D10), R_(D13), and R_(D14) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, orR_(D9) and R_(D10) combine to form a heterocyclyl; or by Formula (V-B)

where

each R_(D2), R_(D3), R_(D17), R_(D18), R_(D19), and R_(D20), isselected, independently from H, halogen, CN, NC, N₃, NO₂, —COR_(D13),—CO₂R_(D13), —CONR_(D13)R_(D14), optionally substituted C₁₋₆ alkyl,optionally substituted aryl, or optionally substituted heteroaryl; and

each R_(D9) and R_(D10) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl, oroptionally substituted aryl, or R_(D9) and R_(D10) combine to form aheterocyclyl;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (V), when R_(D1) and R_(D4) combine toform a double bond, R_(D2) and R_(D3) are H, X_(D1) is NH, X_(D2) is S,Y_(D1) is —(C═O)—, Y_(D2) is —(SO₂)—, G_(D1) is —N(Et)₂, and A is phenylhaving no additional substituents, Y_(D1) and Y_(D2) are not para toeach other.

Compounds of Formula (V) (e.g., compounds of Formula (V-A) or (V-B)) canbe prepared, for example, by treating an aryl or heteroaryl compoundthat has two electrophilic groups successively with nucleophilicreagents to afford the desired compound. For example, as shown in Scheme8 and using procedures adapted from Heterocyclic Communications, 12(6):453-456 (2006) and Organic Synthesis, Collective Vol. 6, page 818, thedifunctional benzene derivative 4-CO₂Hphenylsulfonyl chloride can betreated with a nucleophile such as diethylamine to afford thecorresponding sulfonamide. This compound can then be esterified prior totreatment with a second nucleophile (e.g., methanolic ammonia). Finally,the compound afforded by step (c) can then be condensed with acarbonyl-containing compound to afford compounds of Formula (V) such asCompound (58).

Compounds of Formula (V) (e.g., (V-A) and (V-B) and compound (34)), orany pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof, can also be used as described herein (e.g., inpharmaceutical compositions, as inhibitors of necroptosis, in methods oftreatment, and in kits). In some embodiments, Formulas (V), (V-A), and(V-B) do not include Compounds (58).

Compounds of Formula (VI)

Still other compounds of the invention can be described by Formula (VI)

where

each X_(E1) and X_(E3) is selected, independently, from N or CR_(E4);

each X_(E4) and X_(E5) is selected, independently, from O, S, orNR_(E5);

X_(E2) is selected from O, S, or N;

each Z_(E1), Z_(E2), and Z_(E3) is selected, independently, from asingle bond, —(CR_(E6)R_(E7))_(n)—, —C(O)—, —S(═O)—, or —S(═O)₂—, orZ_(E1)—R_(E2) and Z_(E2)—R_(E2) combine to form a double bond;

each R_(E1), R_(E2), R_(E3), R_(E4), R_(E5), R_(E6), and R_(E7) isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl;

p is 0 or 1; and

n is an integer between 1-6; and

where when X_(E2) is O or S, Z_(E2)—R_(E2) is not present;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, each R_(E1), R_(E2), R_(E3), R_(E4), R_(E5),R_(E6), and R_(E7) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl

In some embodiments, R_(E3) is selected from substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In some embodiments of Formula (VI), when p is 0, X_(E1) is CH,—Z_(E1)—R_(E1) is —CH₂(indol-3-yl), X_(E4) and X_(E5) are O, andX_(E2)—Z_(E2)—R_(E2) is NH, X_(E3)—Z_(E3)—R_(E3) is not —NCH₂(p-ClC₆H₄)or —NCH₂CH₂O(p-FC₆H₄).

In other embodiments, when X_(E1)—Z_(E1)—R_(E1) is NH, X_(E2)—Z_(E2) isCH—CH₂, R_(E2) is unsubstituted 3-indolyl, p is 0, X_(E4) is S, X_(E5)is O, X_(E3) is N, and Z_(E3) is CH₂, R_(E3) is not—CH₂CH₂(4-morpholine).

In still other embodiments, when X_(E1)—Z_(E1)—R_(E1) is NH,X_(E2)—Z_(E2) is CH—CH₂, R_(E2) is unsubstituted or substituted3-indolyl, p is 0 or 1, both X_(E4) and X_(E5) are O or X_(E4) is S andX_(E5) is O, X_(E3) is N, and Z_(E3) is CH₂, R_(E3) is not H,unsubstituted C₁₋₆ alkyl, or —CH₂CH═CH₂.

In any of the compounds of Formula (VI) described herein (e.g., anycompound having a structure according to Formulas (VI), (VI-A), (VI-B),(VI-C), or (VI-D)), the R_(E3) group can be unsubstituted. In someembodiments, a substituted R_(E3) group includes 1, 2, 3, 4, or 5substituents selected from, for example, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl,azido(—N₃), alkoxy (—OR′), amido (—NR′C(═O)R″ or —C(═O)NRR′), amino(—NRR′), carbamoyl (—OC(═O)NR′R″ or —NRC(═O)OR′), hydroxy (—OH), orisocyano (—NC), where each R or R′ is selected, independently, from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cycloalkyl, heterocyclyl, aryl,or heteroaryl. In other embodiments, the substituted R_(E3) groupincludes 1, 2, 3, or 4 substituents that are electron donating groups(e.g., hydroxy, C₁₋₆ alkoxy, C₁₋₆ alkyl, and amino groups).

Certain compounds of Formula (VI) may be described by Formula (VI-A) orFormula (VI-B)

wherein

each Z_(E2) and Z_(E3) is selected, independently, from a single bond,—(CR_(E6)R_(E7))_(n)—, —C(═O)—, or R_(E1) and Z_(E2)—R_(E2) combine toform a double bond;

each R_(E1), R_(E2), R_(E3), and R_(E4) is selected, independently, fromH, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

each R_(E6) and R_(E7) is selected, independently, from H or optionallysubstituted C₁₋₆ alkyl; and

n is an integer between 1-6;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments, each R_(E1), R_(E2), R_(E3), and R_(E4) isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In some embodiments, R_(E3) is selected from substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl.

In some embodiments of Formula (VI-A), when R_(E1) and R_(E4) are H,Z_(E2) and Z_(E3) are each CH₂, and R_(E2) is unsubstituted 3-indolyl,R_(E3) is not 4-chlorophenyl.

In certain embodiments, the compounds of Formula (VI) are described bythe following formula:

where

each X_(E4) and X_(E5) is, independently, O or S;

X_(E2 is O or N;)

each Z_(E2) and Z_(E3) is selected, independently, from a single bond or—(CR_(E6)R_(E7))_(n)—;

each R_(E2) and R_(E3) is, independently, H, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedC₂₋₆ alkenyl, optionally substituted C₂₋₆ alkynyl, optionallysubstituted aryl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl;

each R³ and R⁴ is, independently, H, halogen, or optionally substitutedC₁₋₆ alkyl;

each R⁵, R⁶, R⁷, R⁸, and R⁹ is selected, independently, from H, halogen,CN, NO₂, OR¹³, NR¹³R¹⁴, COR¹⁵, CO₂R¹⁵, optionally substituted C₁₋₆alkyl, or optionally substituted aryl;

R¹⁰ is selected from H, halogen, CN, NO₂, OR¹³, NR¹³R¹⁴, COR¹⁵, CO₂R¹⁵,optionally substituted C₁₋₆ alkyl, optionally substituted aryl,optionally substituted alkenyl, or optionally substituted alkynyl;

each R¹³ and R¹⁴ is selected, independently, from H, COR¹⁶, CO₂R¹⁶,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; and

each R¹¹, R¹², R¹⁵, and R¹⁶ is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; and

where, independently, n is 0, 1, 2, 3, 4, or 5, and p is 0 or 1;

or any pharmaceutically acceptable salt or solvate thereof, orstereoisomer thereof.

In some embodiments, p is 0.

In some embodiments, R_(E3) is selected from substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedaryl, optionally substituted heterocyclyl, or optionally substitutedheteroaryl.

Select compounds of Formula (VI-C) can also be described by Formula(VI-D):

where

X_(E5) is O or S;

—Z_(E3)—R_(E3) is optionally substituted C₁₋₄ alkaryl;

each R³, R⁴, and R¹⁰ is, independently, H or optionally substituted C₁₋₆alkyl;

R⁹ is H, halogen, CN, NO₂, OR¹³, NR¹³R¹⁴, COR¹⁵, CO₂R¹⁵, or optionallysubstituted C₁₋₆ alkyl;

each R¹³ and R¹⁴ is selected, independently, from H, COR¹⁶, CO₂R¹⁶,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; and

each R¹¹, R¹², R¹⁵, and R¹⁶ is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; and

where n is 1 or 2;

or any pharmaceutically acceptable salt or solvate thereof, orstereoisomer thereof.

In some embodiments, the compound has a structure according to thefollowing formula:

or any pharmaceutically acceptable salt or solvate thereof, orstereoisomer thereof, where n, Z_(E3), R_(E3), R³, R⁴, R⁹, and R¹⁰ areas defined for Formula (IV-D).

In the compounds of the invention, the sp³-hybridized carbon to which Gis attached (e.g., the chiral center marked with an asterisk in any ofFormulas (VI-A), (VI-B-1), (VI-B-2), (VI-C), (VI-D), or (VI-E)) can havethe (R)- or the (S)-configuration. For example, compounds of theinvention include

or any pharmaceutically acceptable salt or solvate thereof.

In any embodiment of Formulas (VI-C), (VI-D), or (VI-E), n=1 and R³ andR⁴ are each H. In another embodiment, R¹⁰ is H or CH₃. In still otherembodiments, R⁹ is H, halogen, optionally substituted C₁₋₆ alkyl, OH, or—O-(optionally substituted C₁₋₆ alkyl).

In any embodiment of Formulas (VI-C), (VI-D), or (VI-E), —Z_(E3)—R_(E3)is optionally substituted benzyl. In one embodiment, —Z_(E3)—R_(E3) isunsubstituted benzyl. In another embodiment, —Z_(E3)—R_(E3) is benzylhaving 1, 2, 3, 4, or 5 substituents. In some embodiments, thesubstituents are selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl,heteroaryl, azido(—N₃), alkoxy (—OR′), amido (—NR′C(═O)R″ or—C(═O)NRR′), amino (—NRR′), carbamoyl (—OC(═O)NR′R″ or —NRC(═O)OR′),hydroxy (—OH), and isocyano (—NC), as described herein. In a furtherembodiment, —Z_(E3)—R_(E3) is CH₂— (p-XC₆H₄), where X is halogen. Insome embodiments, X is F or Cl.

In any of the embodiments described herein, one or both of —Z_(E3) andR_(E3) do not include substituents selected from the group consistingof: halogen (e.g., F, Cl, Br, or I); nitro (—NO₂), cyano (—CN),acyloxy(—OC(═O)R′), acyl (—C(═O)R′), carboxylic acid (—CO₂H), carboxylicester (—CO₂R′), sulfonate (—S(═O)₂OR), sulfonamide (—S(═O)₂NRR′ or—NRS(═O)₂R′), or sulfonyl (—S(═O)₂R), where each R or R′ is selected,independently, from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl, as described herein.

Compounds of Formula (VI) (e.g., compounds of Formulas (VI-A), (VI-B),(VI-C), or (VI-D)) can be prepared, for example, by treating hydantoincompound that has, for example, a substituent R at the 5-position with abase followed by trapping with an electrophilic reagent (Scheme 9A). Forexample, Scheme 9B shows that the synthesis of Compound (59) can beachieved by the use of 4-chlorobenzylbromide as the electrophile.

In some embodiments, Formula (VI) (e.g., compounds of Formulas (VI-A),(VI-B), (VI-C), or (VI-D)) does not include any of the compounds orformulas disclosed in U.S. Pat. Nos. 6,756,394 and 7,253,201, in U.S.Patent Publication No. 20050119260, and in pending U.S. application Ser.Nos. 12/077,320 and 12/086,792, each of which is hereby incorporated byreference.

Compounds of Formula (VI) (e.g., (VI-A)-(VI-D) and compound (59)), orany pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof, can also be used as described herein (e.g., inpharmaceutical compositions, as inhibitors of necroptosis, in methods oftreatment, and in kits).

In some embodiments, Formula (VI) does not include compound (59).

Compounds of Formula (VII)

Still other compounds can be described according to Formula (VII)

where

Z_(F1) is selected from a single bond, —(CR_(F10)R_(F11))_(n)—, —C(═O)—,—S(═O)—, or —S(═O)₂—;

each R_(F1), R_(F2), R_(F4), R_(F10), R_(F11), R_(F12), and R_(F13), isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl, or R_(F2) and R_(F4) combine to form a carbon-carbon doublebond;

each R_(F3) and R_(F5) is selected, independently, from H, halogen, CN,CO₂R_(F12), optionally substituted C₁₋₆ alkyl, optionally substitutedC₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl;

each R_(F6), R_(F7), R_(F8), and R_(F9) is selected, independently, fromH, halogen, CN, NC, N₃, NO₂, OR_(F12), SR_(F12), NR_(F12)R_(F13),—COR_(F12), —CO_(2 F12), —CONR_(F12)R_(F13), optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; and

where n is an integer between 1-6;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

Certain compounds of Formula (VII) can also be described by Formula(VII-A)

where

Z_(F1) is selected from a single bond, —(CH₂)—, —C(═O)—, or —S(═O)₂—;

R_(F1) is selected from H, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

R_(F2) and R_(F4) are each H, or R_(F2) and R_(F4) combine to form acarbon-carbon double bond;

each R_(F6), R_(F7), R_(F8), and R_(F9) is selected, independently, fromH, halogen, CN, NC, N₃, NO₂, OR_(F12), SR_(F12), NR_(F12)R_(F13),—COR_(F12), —CO_(2 F12), —CONR_(F12)R_(F13), optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; and

each R_(F12) and R_(F13), is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, oroptionally substituted heteroaryl;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (VII-A), when R_(F2), R_(F4), R_(F6),R_(F7), R_(F8), and R_(F9) are each H and Z_(F1) is —C(═O)—, R_(F1) isnot -(unsubstituted 1,4-benzodioxane) or —CH₂—(O-(unsubstitutedphenyl)).

Scheme 10 provides a method by which compounds of Formula (VII) such asCompound (60) can be prepared. For example, a nucleophilic compound suchas indoline can be treated with an electrophile (e.g., a compoundcontaining a carboxylic acid) in the presence of an optional promotersuch as DEAD/PPh₃ to afford the requisite compound. Another compound ofFormula (VIII) is Compound (61) (Scheme 11).

Compounds of Formula (VII) (e.g., (VII-A) and compound (60)), or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof, can also be used as described herein (e.g., in pharmaceuticalcompositions, as inhibitors of necroptosis, in methods of treatment, andin kits). In some embodiments, Formulas (VII) and (VII-A) do not includecompounds (60) or (61).

Compounds of Formula (VIII)

Still other compounds useful in the invention are described by Formula(VIII):

where

X_(G1) is selected from —O—, —N—, or —(CR_(G9)R_(G10))_(n)—;

X_(G2) and X_(G3) are selected, independently, from N or CR_(G11),

each R_(G1), R_(G2), R_(G3), R_(G4), R_(G5), R_(G6), R_(G7), R_(G8),R_(G9), R_(G10), and R_(G11) is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl, or R_(G1) and R_(G2), orR_(G3) and R_(G4), or R_(G5) and R_(G6), or R_(G7) and R_(G8) combine toform an optionally substituted cycloalkyl or heterocyclyl; and

n is 1 or 2;

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

Select compounds of Formula (VIII) can also be described by Formula(VIII-A):

wherein each R_(G1), R_(G2), R_(G5), and R_(G6) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl, orR_(G1) and R_(G2), or R_(G5) and R_(G6) combine to form an optionallysubstituted cycloalkyl or heterocyclyl,

or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.

In some embodiments of Formula (VIII-A), when R_(G1) is unsubstitutedphenyl and R_(G2) is H, R_(G5) and R_(G6) do not combine to formunsubstituted cyclopentyl,

Methods by which compounds of Formula (VIII) (e.g., compounds of Formula(VIII-A) can be prepared are known in the art. For example, Compound(62) shown in Scheme 12, can be prepared according to methods describedin Synthesis, pages 771-783 (2002).

Compounds of Formula (VIII) (e.g., (VIII-A) and compound (62)), or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof, can also be used as described herein (e.g., in pharmaceuticalcompositions, as inhibitors of necroptosis, in methods of treatment, andin kits).

In some embodiments, Formulas (VIII) and (VIII-A) do not includecompound (62).

Additional Inhibitors of Necroptosis

Other compounds useful in the compositions, kits, and methods of theinvention are described in U.S. Pat. Nos. 6,756,394 and 7,253,201, inU.S. Patent Publication No. 20050119260, and in pending U.S. applicationSer. Nos. 12/077,320 and 12/086,792, each of which is herebyincorporated by reference. In addition to the compounds described byFormulas (I)-(VIII), other inhibitors of necroptosis include, but arenot limited to, the structures depicted in Table 8, or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof.

TABLE 8 Com- pound Structure (63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

Pharmaceutical Compositions

The necrostatins described herein (e.g., compounds of Formulas(I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57),or (58)-(70)) can be formulated into pharmaceutical compositions foradministration to human subjects in a biologically compatible formsuitable for administration in vivo. Accordingly, the present inventionprovides a pharmaceutical composition comprising a compound of theinvention in admixture with a pharmaceutically acceptable excipient.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003-20^(th) edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19),published in 1999.

The compounds may be used in the form of the free base, in the form ofsalts, solvates, and as prodrugs. All forms are within the scope of theinvention. In accordance with the methods of the invention, thedescribed compounds or salts, solvates, or prodrugs thereof may beadministered to a patient in a variety of forms depending on theselected route of administration, as will be understood by those skilledin the art. The compounds of the invention may be administered, forexample, by oral, parenteral, buccal, sublingual, nasal, rectal, patch,pump, or transdermal administration and the pharmaceutical compositionsformulated accordingly. Parenteral administration includes intravenous,intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal,intrapulmonary, intrathecal, rectal, and topical modes ofadministration. Parenteral administration may be by continuous infusionover a selected period of time.

Pharmaceutically Acceptable Excipients

Pharmaceutically acceptable excipients may include, for example:antiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidonc, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol.

Oral Administration

Any of the compounds described herein (e.g., compounds of Formulas(I)-(VIII) or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57),or (58)-(70)) may be orally administered, for example, with an inertdiluent or with an assimilable edible carrier, or it may be enclosed inhard or soft shell gelatin capsules, or it may be compressed intotablets, or it may be incorporated directly with the food of the diet.For oral therapeutic administration, a compound of the invention may beincorporated with an excipient and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like.

Parenteral Administration

A compound may also be administered parenterally. The pharmaceuticalforms suitable for injectable use include sterile aqueous solutions ordispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersions. In all cases the form mustbe sterile and must be fluid to the extent that may be easilyadministered via syringe.

Nasal Administration

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels, and powders. Aerosol formulations typicallyinclude a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomizing device. Alternatively, the sealed container may bea unitary dispensing device, such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal after use. Where the dosage form comprises an aerosoldispenser, it will contain a propellant, which can be a compressed gas,such as compressed air or an organic propellant, such asfluorochlorohydrocarbon. The aerosol dosage forms can also take the formof a pump-atomizer.

Buccal or Sublingual Administration

Compositions suitable for buccal or sublingual administration includetablets, lozenges, and pastilles, where the active ingredient isformulated with a carrier, such as sugar, acacia, tragacanth, or gelatinand glycerine. Compositions for rectal administration are convenientlyin the form of suppositories containing a conventional suppository base,such as cocoa butter.

The compounds of the invention may be administered to an animal alone orin combination with pharmaceutically acceptable carriers, as notedabove, the proportion of which is determined by the solubility andchemical nature of the compound, chosen route of administration, andstandard pharmaceutical practice.

Dosage Amounts

The amount of active ingredient (e.g., a compound of Formulas (I)-(VIII)or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or(58)-(70)) in the compositions of the invention can be varied. Oneskilled in the art will appreciate that the exact individual dosages maybe adjusted somewhat depending upon a variety of factors, including theprotein being administered, the time of administration, the route ofadministration, the nature of the formulation, the rate of excretion,the nature of the subject's conditions, and the age, weight, health, andgender of the patient. Generally, dosage levels of between 0.1 μg/kg to100 mg/kg of body weight are administered daily as a single dose ordivided into multiple doses. Desirably, the general dosage range isbetween 250 μg/kg to 5.0 mg/kg of body weight per day. Wide variationsin the needed dosage are to be expected in view of the differingefficiencies of the various routes of administration. For instance, oraladministration generally would be expected to require higher dosagelevels than administration by intravenous injection. Variations in thesedosage levels can be adjusted using standard empirical routines foroptimization, which are well known in the art. In general, the precisetherapeutically effective dosage will be determined by the attendingphysician in consideration of the above identified factors.

Therapeutic Uses and Screening Methods

The compounds disclosed herein (e.g., compounds of Formulas (I)-(VIII)or any of compounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or(58)-(70)) can be used to treat disorders where necroptosis is likely toplay a substantial role (e.g., cerebral ischemia, traumatic braininjury, a neurodegenerative disease of the central or peripheral nervoussystem, the result of retinal neuronal cell death, the result of celldeath of cardiac muscle, the result of cell death of cells of the immunesystem; stroke, liver disease, pancreatic disease, the result of celldeath associated with renal failure; heart, mesenteric, retinal, hepaticor brain ischemic injury, ischemic injury during organ storage, headtrauma, septic shock, coronary heart disease, cardiomyopathy, myocardialinfarction, bone avascular necrosis, sickle cell disease, musclewasting, gastrointestinal disease, tuberculosis, diabetes, alteration ofblood vessels, muscular dystrophy, graft-versus-host disease, viralinfection, Crohn's disease, ulcerative colitis, asthma, or any conditionin which alteration in cell proliferation, differentiation orintracellular signaling is a causative factor). Compounds of theinvention can also be used in screening methods to identify targets ofnecroptosis and to identify additional inhibitors of necroptosis, aswell as in assay development.

Compounds disclosed herein can be evaluated for their pharmacologicalproperties in animal models of disease. The compounds identified todecrease necrosis or necroptosis may be structurally modified andsubsequently used to decrease necrosis or necroptosis, or to treat asubject with a condition in which necrosis or necroptosis occurs. Themethods used to generate structural derivatives of the small moleculesthat decrease necrosis or necroptosis are readily known to those skilledin the fields of organic and medicinal chemistry.

Therapy according to the invention may be performed alone or inconjunction with another therapy, for example in combination withapoptosis inhibitors, and may be provided at home, the doctor's office,a clinic, a hospital's outpatient department, or a hospital. Treatmentgenerally begins at a hospital so that the doctor can observe thetherapy's effects closely and make any adjustments that are needed. Theduration of the therapy depends on the age and condition of the patient,as well as how the patient responds to the treatment. Additionally, aperson having a greater risk of developing a condition may receiveprophylactic treatment to inhibit or delay symptoms of the disease.

In some embodiments, the compounds and methods of the invention can beused to treat any of the following disorders where necroptosis is likelyto play a substantial role: a neurodegenerative disease of the centralor peripheral nervous system, the result of retinal neuronal cell death,the result of cell death of cardiac muscle, the result of cell death ofcells of the immune system; stroke, liver disease, pancreatic disease,the result of cell death associated with renal failure; heart,mesenteric, retinal, hepatic or brain ischemic injury, ischemic injuryduring organ storage, head trauma, septic shock, coronary heart disease,cardiomyopathy, myocardial infarction, bone avascular necrosis, sicklecell disease, muscle wasting, gastrointestinal disease, tuberculosis,diabetes, alteration of blood vessels, muscular dystrophy,graft-versus-host disease, viral infection, Crohn's disease, ulcerativecolitis, asthma, and any condition in which alteration in cellproliferation, differentiation or intracellular signaling is a causativefactor.

Conditions Caused by Alteration in Cell Proliferation, Differentiation,or Intracellular Signalling

Conditions in which alteration in cell proliferation, differentiation orintracellular signaling is a causative factor include cancer andinfection, e.g., by viruses (e.g., acute, latent and persistent),bacteria, fungi, or other microbes.

Exemplary viruses are human immunodeficiency virus (HIV), Epstein-Barrvirus (EBV), cytomegalovirus (CMV)5 human herpesviruses (HHV), herpessimplex viruses (HSV), human T-Cell leukemia viruses (HTLV)5Varicella-Zoster virus (VZV), measles virus, papovaviruses (JC and BK),hepatitis viruses, adenovirus, parvoviruses, and human papillomaviruses.Exemplary diseases caused by viral infection include, but are notlimited to, chicken pox, Cytomegalovirus infections, genital herpes,Hepatitis B and C, influenza, and shingles.

Exemplary bacteria include, but are not limited to Campylobacter jejuni,Enterobacter species, Enterococcus faecium, Enterococcus faecalis,Escherichia coli (e.g., E. coli O157:H7), Group A streptococci,Haemophilus influenzae, Helicobacter pylori, listeria, Mycobacteriumtuberculosis, Pseudomonas aeruginosa, S. pneumoniae, Salmonella,Shigella, Staphylococcus aureus, and Staphylococcus epidermidis.Exemplary diseases caused by bacterial infection include, but are notlimited to, anthrax, cholera, diphtheria, foodborne illnesses, leprosy,meningitis, peptic ulcer disease, pneumonia, sepsis, tetanus,tuberculosis, typhoid fever, and urinary tract infection.

Neurodegenerative Diseases

Exemplary neurodegenerative diseases are Alzheimer's disease,Huntington's disease, Parkinson's disease, amyotrophic lateralsclerosis, HIV-associated dementia, cerebral ischemia, amyotropiclateral sclerosis, multiple sclerosis, Lewy body disease, Menke'sdisease, Wilson's disease, Creutzfeldt-Jakob disease, and Fahr disease.Exemplary muscular dystrophies or related diseases are Becker's musculardystrophy, Duchenne muscular dystrophy, myotonic dystrophy, limb-girdlemuscular dystrophy, Landouzy-Dejerine muscular dystrophy,facioscapulohumeral muscular dystrophy (Steinert's disease), myotoniacongenita, Thomsen's disease, and Pompe's disease. Muscle wasting can beassociated with cancer, AIDS, congestive heart failure, and chronicobstructive pulmonary disease, as well as include necrotizing myopathyof intensive care.

Compounds and methods of the invention can additionally be used to boostthe immune system, whether or not the patient being treated has animmunocompromising condition. For example, the compounds describedherein can be used in a method to strengthen the immune system duringimmunization, e.g., by functioning as an adjuvant, or by being combinedwith an adjuvant.

Kits

Any of the compounds or pharmaceutical compositions of the invention(e.g., those that include a compound of Formulas (I)-(VIII) or any ofcompounds (1)-(7), (13)-(26), (27)-(33), (48)-(57), or (58)-(70)) can beused together with a set of instructions, i.e., to form a kit. The kitmay include instructions for use of the compounds of the invention in ascreening method or as a therapy as described herein.

The following non-limiting examples are illustrative of the presentinvention.

EXAMPLES Example 1 Determination of Necroptosis Inhibitory Activity

Evaluation of necroptosis inhibitory activity was performed using aFADD-deficient variant of human Jurkat T cells or with L929 cellstreated with TNF-α as previously described (Degterev et al., Nat. Chem.Biol. 1:112 (2005) and Jagtap et al., J. Med. Chem. 50: 1886 (2007)).Utilizing these conditions the cells efficiently underwent necroptosis.For EC₅₀ value determinations, cells were treated with 10 ng/mL of humanTNF-α in the presence of increasing concentration of test compounds for24 hours followed by ATP-based viability assessment.

ATP-based viability assessment: Briefly, necroptosis activity wasperformed using a FADD-deficient variant of human Jurkat T cells or L929cells treated with TNF-α. For EC₅₀ value determinations, cells (500,000cells/mL, 100 μL per well in a 96-well plate) were treated with 10 ng/mLof human TNF-α in the presence of increasing concentration of testcompounds for 24 hours at 37° C. in a humidified incubator with 5% CO₂followed by ATP-based viability assessment. Stock solutions (30 mM) inDMSO were initially prepared and then diluted with DMSO to give testingsolutions, which were added to each test well. The final DMSOconcentration was 0.5%. Eleven compound test concentrations (0.030-100μM) were used. Each concentration was done in duplicate.

Cell viability assessments were performed using a commercial luminescentATP-based assay kit (CellTiter-Glo, Promega, Madison, Wis.) according tothe manufacturer's instructions. Briefly, 40 μL of the cell lysis/ATPdetection reagent was added to each well. Plates were incubated on arocking platform for 10 minutes at room temperature and luminescence wasmeasured using a Wallac Victor 3 plate-reader (Perkin Elmer, Wellesley,Mass.). Cell viability was expressed as a ratio of the signal in thewell treated with TNF-α and compound to the signal in the well treatedwith compound alone. This was done to account for nonspecific toxicity,which in most cases was <10%. EC₅₀ values were calculated usingnonlinear regression analysis of sigmoid dose-response (variable slope)curves from plots of log [I] verses viability values.

Results obtained using these procedures are shown in Table 9.

TABLE 9 EC₅₀ LD₅₀ Compound Fadd −/− EC₅₀ Fadd −/− no. Structure JurkatL929 Jurkat (1)

0.4769 0.1971 >2000 (2)

0.7690 — — (3)

0.8232 — — (4)

0.3540 — — (5)

24.98 — — (6)

Partial activity — — (7)

2.379 — — (8)

inactive (9)

inactive (10)

inactive (11)

inactive (12)

inactive (13)

5.379 0.89 539.4 (14)

0.4101 4.202 396.9 (15)

0.3688 4.02 799.5 (16)

0.6289 72.97 247.7 (17)

incon- clusive — — (18)

0.4101 — — (19)

0.3688 — — (20)

3.211 — — (21)

1.557 — — (22)

Inactive (23)

Inactive (24)

Inactive (25)

Inactive (26)

Inactive (27)

3.227 0.659 541.3 (28)

2.98 — — (29)

31.78 — — (30)

5.833 — — (31)

2.954 — — (32)

2.002 — — (33)

4.788 — — (34)

Inactive (35)

Inactive (36)

Inactive (37)

Inactive (38)

Inactive (39)

Inactive (40)

Inactive (41)

Inactive (42)

Inactive (43)

Inactive (44)

Inactive (45)

Inactive (46)

Inactive (47)

Inactive (48)

0.2161 8.66 188.9 (49)

3.803 — — (50)

>30 — — (51)

10.88 — — (52)

3.046 — — (53)

>30 — — (54)

0.8606 — — (55)

>30 — — (56)

>30 — — (57)

0.9363 — — (58)

8.958 1.11 >2000 (59)

0.3431 7.458 115.7 (60)

0.6289 23.04 356.5 (61)

Inactive (62)

0.6683 10.09 754 (63)

2.364 13.7 1364 (64)

14.14 Inactive 1788 (65)

3.621 Inactive 138.6 (66)

2.616 47.12 256.8 (67)

2.245 10.02 697.8 (68)

1.633 Inactive 252.3 (69)

7.724 Inactive 1571 (70)

0.9077 Inactive >2000

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each independent publication or patent application was specificallyand individually indicated to be incorporated by reference.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Other embodiments are within the claims.

1.-13. (canceled)
 14. A compound having a structure according to thefollowing formula

wherein each R_(A1), R_(A3), and R_(A4) is selected, independently, fromH, optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₆alkenyl, optionally substituted C₂₋₆ alkynyl, optionally substitutedC₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R_(A1) andR_(A4) combine to form a carbon-carbon double bond; G_(A2) is absent or—(CR_(A11)R_(A12))_(n)—; X_(A3) is absent or is O, S, or NR_(A8); eachR_(A8) and R_(A13) is selected, independently, from H, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀ cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, —COR_(A14), —CO₂R_(A14), or—CONR_(A14)R_(A15); each R_(A9), R_(A10), R_(A11), and R_(A12) isselected, independently, from H, halogen, optionally substituted C₁₋₆alkyl, optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; each R_(A7), R_(A14) and R_(A15) is selected, independently,from H, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl; and each m and n is,independently, 1, 2, or 3; and wherein when one of R_(A1) and R_(A4) isH and the other is selected from H or CO₂Et, and R_(A3) is unsubstitutedphenyl, G_(A2)-X_(A3)—R_(A7) is not NHC₆H₅, NH(p-C₆H₄F), NH(p-C₆H₄OH),NH(p-C₆H₄OMe), NH(3-OH-4-Cl—C₆H₄), —CH₂(O-p-C₆H₄Me),—CH₂(4-ethylpiperazinyl), —CH₂S(2-phenyltetrazolyl),—CH₂S(4-chlorophenyl), —CH₂S(2-benzothiazolyl),—CH₂S(2-(N-methylimidazolyl)), —CH₂S(4,6-dimethylquinazolinyl),adamantyl, or optionally substituted oxiranyl; and wherein when R_(A1)and R_(A4) are each H and R_(A3) is 4-methoxyphenyl,G_(A2)-X_(A3)—R_(A7) is not optionally substituted oxiranyl; or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof. 15.-30. (canceled)
 31. A compound having a structure accordingto the following formula

wherein R_(B1) is selected from H, optionally substituted C₁₋₆ alkyl,—C(═O)R_(B18), —C(═O)OR_(B18), or —C(═O)NR_(B18)R_(B19); R_(B2) isselected from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₂₋₆ alkenyl, or optionally substituted C₂₋₆ alkynyl; eachR_(B3) and R_(B4) is selected, independently from H, optionallysubstituted C₁₋₆ alkyl, or R_(B3) and R_(B4) combine to form a bridginggroup having the structure—(CH₂)_(n)—(CR_(B13)═CR_(B14))_(o)—(CH₂)_(p)—; each n, o, and p is,independently, 0 or 1; each R_(B5), R_(B6), R_(B7), R_(B8), R_(B9),R_(B10), R_(B11), and R_(B12) is selected, independently, from H,halogen, —CN, —NO₂, —N₃, —R_(B13), —OR_(B13), —SR_(B13),—NR_(B13)R_(B14), —C(═O)R_(B15), —C(═O)OR_(B15), —C(═O)NR_(B15)R_(B16),—OC(═O)R_(B15), —OC(═O)OR_(B15), —OC(═O)NR_(B15)R_(B16),—NR_(B15)C(═O)R_(B15), —NR_(B15)C(═O)OR_(B16),—NR_(B15)C(═O)NR_(B16)R_(B17), —C(═S)R_(B15), —C(═S)NR_(B15)R_(B16),—NR_(B15)C(═S)R_(B16), —NR_(B15)C(═S)NR_(B16)R_(B17),—C(═NR_(B13))NR_(B15)R_(B16), —NR_(B15)C(═NR_(B13))R_(B16),—NR_(B15)C(═NR_(B13))NR_(B16)R_(B17); each R_(B13) and R_(B14) isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substituted aryl,optionally substituted heteroaryl, —C(═O)R_(B18), —C(═O)OR_(B18), or—C(═O)NR_(B18)R_(B19), each R_(B15), R_(B16), R_(B17), R_(B18), andR_(B19) is selected, independently, from H, optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedaryl, or optionally substituted heteroaryl; wherein when each n, o, andp is 0, R_(B3) and R_(B4) combine to form a single bond, and whereinR_(B1) is not H or CH₃ when R_(B5), R_(B6), R_(B7), R_(B8), R_(B9),R_(B10), R_(B11), and R_(B12) are each H, R_(B2) is ethyl, ethenyl,2-haloethenyl, ethynyl, haloethynyl, propynyl, or —C≡C—C(OH)(CH₃)₂, andwhen R_(B3) and R_(B4) are each H or combine to form a bond, —CH₂CH₂— or—CH═CH—; wherein R_(B1) is not H when R_(B5), R_(B6), R_(B7), R_(B8),R_(B10), and R_(B11) are each H, at least one of R_(B9) or R_(B12) isfluoro, R_(B2) is ethynyl, and when R_(B3) and R_(B4) combine to form—CH₂CH₂—; wherein R_(B1) is not H when R_(B5), R_(B7), R_(B9), andR_(B11) are H and one or two of R_(B6), R_(B8), R_(B10), and R_(B12) ishalogen, nitro, or methyl; and or any pharmaceutically acceptable saltor solvate thereof, or any stereoisomer thereof. 32.-39. (canceled) 40.A compound having a structure according to the following formula

wherein each R_(C1), R_(C2), and R_(C3) is selected, independently, fromH, optionally substituted C₁₋₆ alkyl, —Y—R_(C7), or R_(C1) and R_(C2)combine to form a (═O) or a (═S) group, or R_(C1) and R_(C3) combine toform a carbon-nitrogen double bond; R_(C4) is selected from H, halogen,—CN, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, optionally substituted heteroaryl, or —C(═O)ZR_(C8), each R_(C5)and R_(C6) is selected, independently, from H, optionally substitutedC₁₋₆ alkyl, or R_(C5) and R_(C6) combine to form an optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; eachR_(C7), R_(C8), R_(C9), R_(C10), R_(C11), and R_(C12) is selected,independently, from H, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₃₋₁₀ cycloalkyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; X is—CR_(C11)—CR_(C12)—, O, S, or NR_(C9); Y is, independently, a singlebond, (CR_(C8)R_(C9))_(n), O, S, or NR_(C10); and Z is a single bond, O,S, or NR_(C10); n is an integer between 0-4; and wherein when X is S,R_(C1) and R_(C2) combine to form a (═O) group, R_(C4) is H, and R_(C5)and R_(C6) combine to form unsubstituted cyclopentyl, R_(C3) is not—CH₂—R_(C7), where R_(C7) is unsubstituted phenyl, unsubstitutednaphthyl, unsubstituted 8-quinolyl, unsubstituted 2-oxoquinolyl, orphenyl having 1 or 2 substituents selected from F, OMe, Me, CN, or Cl;wherein when X is S, R_(C1) and R_(C2) combine to form a (═O) group,R_(C4) is H, and R_(C5) and R_(C6) are each CH₃, R_(C3) is not—CH₂—R_(C7), where R_(C7) is unsubstituted phenyl; and wherein when X isCH═CH, R_(C1) and R_(C2) combine to form a (═O) group, R_(C4) is H, andR_(C5) and R_(C6) are H, R_(C3) is not —CH₂(4-halophenyl); or anypharmaceutically acceptable salt or solvate thereof, or any stereoisomerthereof.
 41. (canceled)
 42. The compound of claim 40, wherein saidcompound has a structure according to the following formula

wherein X, R_(C1), R_(C2), R_(C3), and R_(C4) are as defined for Formula(IV) and n is an integer between 0-3, or any pharmaceutically acceptablesalt or solvate thereof, or any stereoisomer thereof.
 43. The compoundof claim 42, wherein R_(C1) and R_(C2) combine to form a (═O) group, orany pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.
 44. The compound of claim 42, wherein X is S, orany pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.
 45. The compound of claim 42, wherein n is 1, orany pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof.
 46. The compound of claim 45, wherein R_(C3) is—Y—R_(C7), or any pharmaceutically acceptable salt or solvate thereof,or any stereoisomer thereof.
 47. The compound of claim 46, whereinR_(C3) is —(CH₂)-(optionally substituted aryl), or any pharmaceuticallyacceptable salt or solvate thereof, or any stereoisomer thereof. 48.-54.(canceled)
 55. A compound having a structure according to one of thefollowing formulas

wherein each Z_(E2) and Z_(E3) is selected, independently, from a singlebond, —(CR_(E6)R_(E7))_(n)—, —C(═O)—, or R_(E1) and Z_(E2)—R_(E2)combine to form a double bond; each R_(E1), R_(E2), and R_(E4) isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; R_(E3) is selected from optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; each R_(E6) and R_(E7) isselected, independently, from H or optionally substituted C₁₋₆ alkyl;and each n is an integer between 1-6; and wherein when R_(E1) and R_(E4)are H, Z_(E2) and Z_(E3) are each CH₂, and R_(E2) is unsubstituted3-indolyl, R_(E3) is not 4-chlorophenyl or CH₂CH₂O(p-C₆H₄F); or

wherein each Z_(E2) and Z_(E3) is selected, independently, from a singlebond, —(CR_(E6)R_(E7))_(n)—, —C(═O)—, or E_(E1) and Z_(E2)—R_(E2)combine to form a double bond; each R_(E1), R_(E2), and R_(E4) isselected, independently, from H, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; R_(E3) is selected from optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; each R_(E6) and R_(E7) isselected, independently, from H or optionally substituted C₁₋₆ alkyl;and each n is an integer between 1-6; and wherein when R_(E1) and R_(E4)are H, Z_(E2) is CH₂, and Z_(E3) is CH₂CH₂, R_(E2) is unsubstituted3-indolyl, R_(E3) is not 4-morpholine, or any pharmaceuticallyacceptable salt or solvate thereof, or any stereoisomer thereof.
 56. Thecompound of claim 55, wherein said compound has a structure according toone of the following formulas:

wherein R_(E3) is optionally substituted aryl or optionally substitutedheteroaryl; and R⁹ is H, halogen, CN, NO₂, OR¹³, NR¹³R¹⁴, COR¹⁵, CO₂R¹⁵,or optionally substituted C₁₋₆ alkyl; each R¹³ and R¹⁴ is selected,independently, from H, COR¹⁶, CO₂R¹⁶, optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; and, each R¹⁵ and R¹⁶ is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; or

wherein R_(E3) is optionally substituted aryl or optionally substitutedheteroaryl; and R⁹ is H, halogen, CN, NO₂, OR¹³, NR¹³R¹⁴, COR¹⁵, CO₂R¹⁵or optionally substituted C₁₋₆ alkyl; each R¹³ and R¹⁴ is selected,independently, from H, COR¹⁶, CO₂R¹⁶ optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₁₀ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl; and, each R¹⁵ and R¹⁶ is selected, independently, from H,optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₁₀cycloalkyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl; or any pharmaceuticallyacceptable salt or solvate thereof, or any stereoisomer thereof. 57.-58.(canceled)
 59. The compound of claim 55, wherein R_(E3) is unsubstitutedC₃₋₁₀ cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, orunsubstituted heteroaryl; or any pharmaceutically acceptable salt orsolvate thereof, or any stereoisomer thereof.
 60. (canceled)
 61. Thecompound of claim 55, wherein R_(E3) is substituted C₃₋₁₀ cycloalkyl,substituted heterocyclyl, substituted aryl, or substituted heteroaryl;or any pharmaceutically acceptable salt or solvate thereof, or anystereoisomer thereof. 62.-63. (canceled)
 64. The compound of claim 61,wherein R_(E3) is substituted phenyl, or any pharmaceutically acceptablesalt or solvate thereof, or any stereoisomer thereof. 65.-66. (canceled)67. The compound of claim 55, wherein the stereocenter marked by theasterisk has the (R)-configuration, or any pharmaceutically acceptablesalt or solvate thereof, or any stereoisomer thereof.
 68. The compoundof claim 55, wherein the stereocenter marked by the asterisk has the(S)-configuration, or any pharmaceutically acceptable salt or solvatethereof, or any stereoisomer thereof. 69.-79. (canceled)
 80. Apharmaceutical composition comprising a pharmaceutically acceptableexcipient and the compound of claim 40, or any pharmaceuticallyacceptable salt or solvate thereof, or stereoisomer thereof. 81.(canceled)
 82. A method of treating a condition in a subject, saidmethod comprising the step of administering the compound of claim 40, orany pharmaceutically acceptable salt or solvate thereof, or stereoisomerthereof, to said subject in a dosage sufficient to decrease necroptosis.83. (canceled)
 84. The method of claim 82, wherein said condition is aneurodegenerative disease of the central or peripheral nervous system,the result of retinal neuronal cell death, the result of cell death ofcardiac muscle, the result of cell death of cells of the immune system;stroke, liver disease, pancreatic disease, the result of cell deathassociated with renal failure; heart, mesenteric, retinal, hepatic orbrain ischemic injury, ischemic injury during organ storage, headtrauma, septic shock, coronary heart disease, cardiomyopathy, myocardialinfarction, bone avascular necrosis, sickle cell disease, musclewasting, gastrointestinal disease, tuberculosis, diabetes, alteration ofblood vessels, muscular dystrophy, graft-versus-host disease, viralinfection, Crohn's disease, ulcerative colitis, asthma, or any conditionin which alteration in cell proliferation, differentiation orintracellular signaling is a causative factor. 85.-88. (canceled)
 89. Amethod of decreasing necroptosis comprising contacting a cell with thecompound of claim 40, or any pharmaceutically acceptable salt or solvatethereof, or stereoisomer thereof. 90.-92. (canceled)